Process for preparing [(3-hydroxypyridine-2-carbonyl)amino]alkanoic acids, esters and amides

ABSTRACT

Disclosed are processes for preparing [(3-hydroxypyridine-2-carbonyl)amino]-alkanoic acids, derivatives, inter alia, 5-aryl substituted and 5-heteroaryl substituted [(3-hydroxypyridine-2-carbonyl]amino}acetic acids. Further disclosed are methods for making prodrugs of [(3-hydroxypyridine-2-carbonyl)-amino]acetic acids, for example, [(3-hydroxypyridine-2-carbonyl]amino}acetic acid esters and {[3-hydroxypyridine-2-carbonyl]amino}acetic acid amides. The disclosed compounds are useful as prolyl hydroxylase inhibitors or for treating conditions wherein prolyl hydroxylase inhibition is desired.

PRIORITY

This application is a divisional of U.S. application Ser. No.13/488,554, filed Jun. 5, 2012, currently allowed, which claims thebenefit of U.S. Provisional Application No. 61/493,536, filed Jun. 6,2011, the entirety of which are included herein by reference.

FIELD

Disclosed are processes for preparing[(3-hydroxypyridine-2-carbonyl)amino]-alkanoic acids, derivatives, interalia, 5-aryl substituted and 5-heteroaryl substituted[(3-hydroxypyridine-2-carbonyl]amino}acetic acids. Further disclosed aremethods for making prodrugs of[(3-hydroxypyridine-2-carbonyl)-amino]acetic acids, for example,[(3-hydroxypyridine-2-carbonyl]amino}acetic acid esters and{[3-hydroxypyridine-2-carbonyl]amino}acetic acid amides. The disclosedcompounds are useful as prolyl hydroxylase inhibitors or for treatingconditions wherein prolyl hydroxylase inhibition is desired.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 depicts an outline of one embodiment for preparing the disclosedprolyl hydroxylase inhibitors.

FIG. 2 depicts an outline of one embodiment for preparing the disclosedprolyl hydroxylase inhibitor ester prodrugs.

FIG. 3 depicts an outline of one embodiment for preparing the disclosedprolyl hydroxylase inhibitor amide prodrugs.

DETAILED DISCLOSURE

The materials, compounds, compositions, articles, and methods describedherein may be understood more readily by reference to the followingdetailed description of specific aspects of the disclosed subject matterand the Examples included therein.

Before the present materials, compounds, compositions, articles,devices, and methods are disclosed and described, it is to be understoodthat the aspects described below are not limited to specific syntheticmethods or specific reagents, as such may, of course, vary. It is alsoto be understood that the terminology used herein is for the purpose ofdescribing particular aspects only and is not intended to be limiting.

Also, throughout this specification, various publications arereferenced. The disclosures of these publications in their entiretiesare hereby incorporated by reference into this application in order tomore fully describe the state of the art to which the disclosed matterpertains. The references disclosed are also individually andspecifically incorporated by reference herein for the material containedin them that is discussed in the sentence in which the reference isrelied upon.

GENERAL DEFINITIONS

In this specification and in the claims that follow, reference will bemade to a number of terms, which shall be defined to have the followingmeanings.

All percentages, ratios and proportions herein are by weight, unlessotherwise specified. All temperatures are in degrees Celsius (° C.)unless otherwise specified.

By “pharmaceutically acceptable” is meant a material that is notbiologically or otherwise undesirable, i.e., the material can beadministered to an individual along with the relevant active compoundwithout causing clinically unacceptable biological effects orinteracting in a deleterious manner with any of the other components ofthe pharmaceutical composition in which it is contained.

A weight percent of a component, unless specifically stated to thecontrary, is based on the total weight of the formulation or compositionin which the component is included.

“Admixture” or “blend” is generally used herein means a physicalcombination of two or more different components.

Throughout the description and claims of this specification the word“comprise” and other forms of the word, such as “comprising” and“comprises,” means including but not limited to, and is not intended toexclude, for example, other additives, components, integers, or steps.

As used in the description and the appended claims, the singular forms“a,” “an,” and “the” include plural referents unless the context clearlydictates otherwise. Thus, for example, reference to“[(3-hydroxypyridine-2-carbonyl)amino]alkanoic acid” includes mixturesof two or more such [(3-hydroxypyridine-2-carbonyl)amino]alkanoic acids,reference to “the compound” includes mixtures of two or more suchcompounds, which can include mixtures of optical isomers (racemicmixtures), and the like.

“Optional” or “optionally” means that the subsequently described eventor circumstance can or cannot occur, and that the description includesinstances where the event or circumstance occurs and instances where itdoes not.

Ranges can be expressed herein as from “about” one particular value,and/or to “about” another particular value. When such a range isexpressed, another aspect includes from the one particular value and/orto the other particular value. Similarly, when values are expressed asapproximations, by use of the antecedent “about,” it will be understoodthat the particular value forms another aspect. It will be furtherunderstood that the endpoints of each of the ranges are significant bothin relation to the other endpoint, and independently of the otherendpoint. It is also understood that there are a number of valuesdisclosed herein, and that each value is also herein disclosed as“about” that particular value in addition to the value itself. Forexample, if the value “10” is disclosed, then “about 10” is alsodisclosed. It is also understood that when a value is disclosed, then“less than or equal to” the value, “greater than or equal to the value,”and possible ranges between values are also disclosed, as appropriatelyunderstood by the skilled artisan. For example, if the value “10” isdisclosed, then “less than or equal to 10” as well as “greater than orequal to 10” is also disclosed. It is also understood that throughoutthe application data are provided in a number of different formats andthat this data represent endpoints and starting points and ranges forany combination of the data points. For example, if a particular datapoint “10” and a particular data point “15” are disclosed, it isunderstood that greater than, greater than or equal to, less than, lessthan or equal to, and equal to 10 and 15 are considered disclosed aswell as between 10 and 15. It is also understood that each unit betweentwo particular units are also disclosed. For example, if 10 and 15 aredisclosed, then 11, 12, 13, and 14 are also disclosed.

The following chemical hierarchy is used throughout the specification todescribe and enable the scope of the present disclosure and toparticularly point out and distinctly claim the units which comprise thecompounds of the present disclosure, however, unless otherwisespecifically defined, the terms used herein are the same as those of theartisan of ordinary skill. The term “hydrocarbyl” stands for any carbonatom-based unit (organic molecule), said units optionally containing oneor more organic functional group, including inorganic atom comprisingsalts, inter alia, carboxylate salts, quaternary ammonium salts. Withinthe broad meaning of the term “hydrocarbyl” are the classes “acyclichydrocarbyl” and “cyclic hydrocarbyl” which terms are used to dividehydrocarbyl units into cyclic and non-cyclic classes.

As it relates to the following definitions, “cyclic hydrocarbyl” unitscan comprise only carbon atoms in the ring (i.e., carbocyclic and arylrings) or these units can comprise one or more heteroatoms in the ring(i.e., heterocyclic and heteroaryl rings). For “carbocyclic” rings thelowest number of carbon atoms in a ring is 3 carbon atoms; cyclopropyl.For “aryl” rings the lowest number of carbon atoms in a ring are 6carbon atoms; phenyl. For “heterocyclic” rings the lowest number ofcarbon atoms in a ring is 1 carbon atom; diazirinyl, a C₁ heterocyclicring. Ethylene oxide comprises 2 carbon atoms and is a C₂ heterocyclicring. For “heteroaryl” rings the lowest number of carbon atoms in a ringis 1 carbon atom; 1,2,3,4-tetrazolyl, a C₁ heteroaryl ring. The terms“heterocycle” and “heterocyclic ring” can also include “heteroarylrings.” The following is a non-limiting description of the unitsencompassed by the terms “acyclic hydrocarbyl” and “cyclic hydrocarbyl”as used herein.

A. Substituted and unsubstituted acyclic hydrocarbyl:

-   -   For the purposes of the present disclosure the term “substituted        and unsubstituted acyclic hydrocarbyl” encompasses 3 categories        of units:

-   1) linear or branched alkyl, non-limiting examples of which include,    methyl (C₁), ethyl (C₂), n-propyl (C₃), iso-propyl (C₃), n-butyl    (C₄), sec-butyl (C₄), iso-butyl (C₄), tert-butyl (C₄), and the like;    substituted linear or branched alkyl, non-limiting examples of which    includes, hydroxymethyl (C₁), chloromethyl (C₁), trifluoromethyl    (C₁), aminomethyl (C₁), 1-chloroethyl (C₂), 2-hydroxyethyl (C₂),    1,2-difluoroethyl (C₂), 3-carboxypropyl (C₃), and the like.

-   2) linear or branched alkenyl, non-limiting examples of which    include, ethenyl (C₂), 3-propenyl (C₃), 1-propenyl (also    2-methylethenyl) (C₃), isopropenyl (also 2-methylethen-2-yl) (C₃),    buten-4-yl (C₄), and the like; substituted linear or branched    alkenyl, non-limiting examples of which include, 2-chloroethenyl    (also 2-chlorovinyl) (C₂), 4-hydroxybuten-1-yl (C₄),    7-hydroxy-7-methyloct-4-en-2-yl (C₉),    7-hydroxy-7-methyloct-3,5-dien-2-yl (C₉), and the like.

-   3) linear or branched alkynyl, non-limiting examples of which    include, ethynyl (C₂), prop-2-ynyl (also propargyl) (C₃),    propyn-1-yl (C₃), and 2-methyl-hex-4-yn-1-yl (C₇); substituted    linear or branched alkynyl, non-limiting examples of which include,    5-hydroxy-5-methylhex-3-ynyl (C₇), 6-hydroxy-6-methylhept-3-yn-2-yl    (C₈), 5-hydroxy-5-ethylhept-3-ynyl (C₉), and the like.    B. Substituted and unsubstituted cyclic hydrocarbyl:    -   For the purposes of the present disclosure the term “substituted        and unsubstituted cyclic hydrocarbyl” encompasses 5 categories        of units:

-   1) The term “carbocyclic” is defined herein as “encompassing rings    comprising from 3 to 20 carbon atoms, in one embodiment from 3 to 10    carbon atoms, in another embodiment from 3 to 7 carbon atoms, in a    still further embodiment 5 or 6 carbon atoms, wherein the atoms    which comprise said rings are limited to carbon atoms, and further    each ring can be independently substituted with one or more moieties    capable of replacing one or more hydrogen atoms.” The following are    non-limiting examples of “substituted and unsubstituted carbocyclic    rings” which encompass the following categories of units:    -   i) carbocyclic rings having a single substituted or        unsubstituted hydrocarbon ring, non-limiting examples of which        include, cyclopropyl (C₃), 2-methyl-cyclopropyl (C₃),        cyclopropenyl (C₃), cyclobutyl (C₄), 2,3-dihydroxycyclobutyl        (C₄), cyclobutenyl (C₄), cyclopentyl (C₅), cyclopentenyl (C₅),        cyclopentadienyl (C₅), cyclohexyl (C₆), cyclohexenyl (C₆),        cycloheptyl (C₇), cyclooctanyl (C₈), 2,5-dimethylcyclopentyl        (C₅), 3,5-dichlorocyclohexyl (C₆), 4-hydroxycyclohexyl (C₆), and        3,3,5-trimethylcyclohex-1-yl (C₆).    -   ii) carbocyclic rings having two or more substituted or        unsubstituted fused hydrocarbon rings, non-limiting examples of        which include, octahydropentalenyl (C₈), octahydro-1H-indenyl        (C₉), 3a,4,5,6,7,7a-hexahydro-3H-inden-4-yl (C₉),        decahydroazulenyl (C₁₀).    -   iii) carbocyclic rings which are substituted or unsubstituted        bicyclic hydrocarbon rings, non-limiting examples of which        include, bicyclo-[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl,        bicyclo[3.1.1]heptanyl, 1,3-dimethyl[2.2.1]heptan-2-yl,        bicyclo[2.2.2]octanyl, and bicyclo[3.3.3]undecanyl.

-   2) The term “aryl” is defined herein as “units encompassing at least    one phenyl or naphthyl ring and wherein there are no heteroaryl or    heterocyclic rings fused to the phenyl or naphthyl ring and further    each ring can be independently substituted with one or more moieties    capable of replacing one or more hydrogen atoms.” The following are    non-limiting examples of “substituted and unsubstituted aryl rings”    which encompass the following categories of units:    -   i) C₆ or C₁₀ substituted or unsubstituted aryl rings; phenyl and        naphthyl rings whether substituted or unsubstituted,        non-limiting examples of which include, phenyl (C₆),        naphthylen-1-yl (C₁₀), naphthylen-2-yl (C₁₀), 4-fluorophenyl        (C₆), 2-hydroxyphenyl (C₆), 3-methylphenyl (C₆),        2-amino-4-fluorophenyl (C₆), 2-(N,N-diethylamino)phenyl (C₆),        2-cyanophenyl (C₆), 2,6-di-tert-butylphenyl (C₆),        3-methoxyphenyl (C₆), 8-hydroxynaphthylen-2-yl (C₁₀),        4,5-dimethoxynaphthylen-1-yl (C₁₀), and 6-cyano-naphthylen-1-yl        (C₁₀).    -   ii) C₆ or C₁₀ aryl rings fused with 1 or 2 saturated rings to        afford C₈-C₂₀ ring systems, non-limiting examples of which        include, bicyclo[4.2.0]octa-1,3,5-trienyl (C₈), and indanyl        (C₉).

-   3) The terms “heterocyclic” and/or “heterocycle” are defined herein    as “units comprising one or more rings having from 3 to 20 atoms    wherein at least one atom in at least one ring is a heteroatom    chosen from nitrogen (N), oxygen (O), or sulfur (S), or mixtures of    N, O, and S, and wherein further the ring which contains the    heteroatom is also not an aromatic ring.” The following are    non-limiting examples of “substituted and unsubstituted heterocyclic    rings” which encompass the following categories of units:    -   i) heterocyclic units having a single ring containing one or        more heteroatoms, non-limiting examples of which include,        diazirinyl (C₁), aziridinyl (C₂), urazolyl (C₂), azetidinyl        (C₃), pyrazolidinyl (C₃), imidazolidinyl (C₃), oxazolidinyl        (C₃), isoxazolinyl (C₃), thiazolidinyl (C₃), isothiazolinyl        (C₃), oxathiazolidinonyl (C₃), oxazolidinonyl (C₃), hydantoinyl        (C₃), tetrahydrofuranyl (C₄), pyrrolidinyl (C₄), morpholinyl        (C₄), piperazinyl (C₄), piperidinyl (C₄), dihydropyranyl (C₅),        tetrahydropyranyl (C₅), piperidin-2-onyl (valerolactam) (C₅),        2,3,4,5-tetrahydro-1H-azepinyl (C₆), 2,3-dihydro-1H-indole (C₈),        and 1,2,3,4-tetrahydroquinoline (C₉).    -   ii) heterocyclic units having 2 or more rings one of which is a        heterocyclic ring, non-limiting examples of which include        hexahydro-1H-pyrrolizinyl (C₇),        3a,4,5,6,7,7a-hexahydro-1H-benzo[d]imidazolyl (C₇),        3a,4,5,6,7,7a-hexahydro-1H-indolyl (C₈),        1,2,3,4-tetrahydroquinolinyl (C₉), and        decahydro-1H-cycloocta[b]pyrrolyl (C₁₀).

-   4) The term “heteroaryl” is defined herein as “encompassing one or    more rings comprising from 5 to 20 atoms wherein at least one atom    in at least one ring is a heteroatom chosen from nitrogen (N),    oxygen (O), or sulfur (S), or mixtures of N, O, and S, and wherein    further at least one of the rings which comprises a heteroatom is an    aromatic ring.” Heteroaryl rings can comprise from 1 to 19 carbon    atoms, in another embodiment heteroaryl rings can comprise from 1 to    9 carbon atoms. The following are non-limiting examples of    “substituted and unsubstituted heterocyclic rings” which encompass    the following categories of units:    -   i) heteroaryl rings containing a single ring, non-limiting        examples of which include, 1,2,3,4-tetrazolyl (C₁),        [1,2,3]triazolyl (C₂), [1,2,4]triazolyl (C₂), triazinyl (C₃),        thiazolyl (C₃), 1H-imidazolyl (C₃), oxazolyl (C₃), isoxazolyl        (C₃), isothiazolyl (C₃), furanyl (C₄), thiophenyl (C₄),        pyrimidinyl (C₄), 2-phenylpyrimidinyl (C₄), pyridinyl (C₅),        3-methylpyridinyl (C₅), and 4-dimethylaminopyridinyl (C₅)    -   ii) heteroaryl rings containing 2 or more fused rings one of        which is a heteroaryl ring, non-limiting examples of which        include: 7H-purinyl (C₅), 9H-purinyl (C₅), 6-amino-9H-purinyl        (C₅), 5H-pyrrolo[3,2-d]pyrimidinyl (C₆),        7H-pyrrolo[2,3-d]pyrimidinyl (C₆), pyrido[2,3-d]pyrimidinyl        (C₇), 2-phenylbenzo[d]thiazolyl (C₇), 1H-indolyl (C₈),        4,5,6,7-tetrahydro-1-H-indolyl (C₈), quinoxalinyl (C₈),        5-methylquinoxalinyl (C₈), quinazolinyl (C₈), quinolinyl (C₉),        8-hydroxy-quinolinyl (C₉), and isoquinolinyl (C₉).    -   5) C₁-C₆ tethered cyclic hydrocarbyl units (whether carbocyclic        units, C₆ or C₁₀ aryl units, heterocyclic units, or heteroaryl        units) which connected to another moiety, unit, or core of the        molecule by way of a C₁-C₆ alkylene unit. Non-limiting examples        of tethered cyclic hydrocarbyl units include benzyl C₁—(C₆)        having the formula:

-   -   -   wherein R^(a) is optionally one or more independently chosen            substitutions for hydrogen. Further examples include other            aryl units, inter alia, (2-hydroxyphenyl)hexyl C₆—(C₆);            naphthalen-2-ylmethyl C₁—(C₁₀), 4-fluorobenzyl C₁—(C₆),            2-(3-hydroxyphenyl)ethyl C₂—(C₆), as well as substituted and            unsubstituted C₃-C₁₀ alkylenecarbocyclic units, for example,            cyclopropylmethyl C₁—(C₃), cyclopentylethyl C₂—(C₅),            cyclohexylmethyl C₁—(C₆). Included within this category are            substituted and unsubstituted C₁-C₁₀ alkylene-heteroaryl            units, for example a 2-picolyl C₁—(C₆) unit having the            formula:

-   -   -   wherein R^(a) is the same as defined above. In addition,            C₁-C₁₂ tethered cyclic hydrocarbyl units include C₁-C₁₀            alkyleneheterocyclic units and alkylene-heteroaryl units,            non-limiting examples of which include, aziridinylmethyl            C₁—(C₂) and oxazol-2-ylmethyl C₁—(C₃).

For the purposes of the present disclosure carbocyclic rings are from C₃to C₂₀; aryl rings are C₆ or C₁₀; heterocyclic rings are from C₁ to C₉;and heteroaryl rings are from C₁ to C₉.

For the purposes of the present disclosure, and to provide consistencyin defining the present disclosure, fused ring units, as well asspirocyclic rings, bicyclic rings and the like, which comprise a singleheteroatom will be characterized and referred to herein as beingencompassed by the cyclic family corresponding to the heteroatomcontaining ring, although the artisan may have alternativecharacterizations. For example, 1,2,3,4-tetrahydroquinoline having theformula:

is, for the purposes of the present disclosure, defined as aheterocyclic unit. 6,7-Dihydro-5H-cyclopentapyrimidine having theformula:

is, for the purposes of the present disclosure, is defined as aheteroaryl unit. When a fused ring unit contains heteroatoms in both anon-aromatic ring (heterocyclic ring) and an aryl ring (heteroarylring), the aryl ring will predominate and determine the type of categoryto which the ring is assigned herein for the purposes of describing theinvention. For example, 1,2,3,4-tetrahydro-[1,8]naphthpyridine havingthe formula:

is, for the purposes of the present disclosure, is defined as aheteroaryl unit.The term “substituted” is used throughout the specification. The term“substituted” is applied to the units described herein as “substitutedunit or moiety is a hydrocarbyl unit or moiety, whether acyclic orcyclic, which has one or more hydrogen atoms replaced by a substituentor several substituents as defined herein below.” The units, whensubstituting for hydrogen atoms are capable of replacing one hydrogenatom, two hydrogen atoms, or three hydrogen atoms of a hydrocarbylmoiety at a time. In addition, these substituents can replace twohydrogen atoms on two adjacent carbons to form said substituent, newmoiety, or unit. For example, a substituted unit that requires a singlehydrogen atom replacement includes halogen, hydroxyl, and the like. Atwo hydrogen atom replacement includes carbonyl, oximino, and the like.A two hydrogen atom replacement from adjacent carbon atoms includesepoxy, and the like. Three hydrogen replacement includes cyano, and thelike. The term substituted is used throughout the present specificationto indicate that a hydrocarbyl moiety, inter alia, aromatic ring, alkylchain; can have one or more of the hydrogen atoms replaced by asubstituent. When a moiety is described as “substituted” any number ofthe hydrogen atoms may be replaced. For example, 4-hydroxyphenyl is a“substituted aromatic carbocyclic ring (aryl ring)”,(N,N-dimethyl-5-amino)octanyl is a “substituted C₈ linear alkyl unit,3-guanidinopropyl is a “substituted C₃ linear alkyl unit,” and2-carboxypyridinyl is a “substituted heteroaryl unit.”

The following are non-limiting examples of units which can substitutefor hydrogen atoms on a carbocyclic, aryl, heterocyclic, or heteroarylunit:

-   -   i) substituted or unsubstituted C₁-C₁₂ linear, C₃-C₁₂ branched,        or C₃-C₁₂ cyclic alkyl, alkenyl, and alkynyl; methyl (C₁), ethyl        (C₂), ethenyl (C₂), ethynyl (C₂), n-propyl (C₃), iso-propyl        (C₃), cyclopropyl (C₃), 3-propenyl (C₃), 1-propenyl (also        2-methylethenyl) (C₃), isopropenyl (also 2-methylethen-2-yl)        (C₃), prop-2-ynyl (also propargyl) (C₃), propyn-1-yl (C₃),        n-butyl (C₄), sec-butyl (C₄), iso-butyl (C₄), tert-butyl (C₄),        cyclobutyl (C₄), buten-4-yl (C₄), cyclopentyl (C₅), cyclohexyl        (C₆);    -   ii) substituted or unsubstituted C₆ or C₁₀ aryl; for example,        phenyl, naphthyl (also referred to herein as naphthylen-1-yl        (C₁₀) or naphthylen-2-yl (C₁₀));    -   iii) substituted or unsubstituted C₇ or C₁₁ alkylenearyl; for        example, benzyl, 2-phenylethyl, naphthylen-2-ylmethyl;    -   iv) substituted or unsubstituted C₁-C₉ heterocyclic rings; as        described herein below;    -   v) substituted or unsubstituted C₁-C₉ heteroaryl rings; as        described herein below;    -   vi) —(CR^(102a)R^(102b))_(a)OR¹⁰¹; for example, —OH, —CH₂OH,        —OCH₃, —CH₂OCH₃, —OCH₂CH₃, —CH₂OCH₂CH₃, —OCH₂CH₂CH₃, and        —CH₂OCH₂CH₂CH₃;    -   vii) —(CR^(102a)R^(102b))_(a)C(O)R¹⁰¹; for example, —COCH₃,        —CH₂COCH₃, —COCH₂CH₃, —CH₂COCH₂CH₃, —COCH₂CH₂CH₃, and        —CH₂COCH₂CH₂CH₃;    -   viii) —(CR^(102a)R^(102b))_(a)C(O)OR¹⁰¹; for example, —CO₂CH₃,        —CH₂CO₂CH₃, —CO₂CH₂CH₃, —CH₂CO₂CH₂CH₃, —CO₂CH₂CH₂CH₃, and        —CH₂CO₂CH₂CH₂CH₃;    -   ix) —(CR^(102a)R^(102b))_(a)C(O)N(R¹⁰¹)₂; for example, —CONH₂,        —CH₂CONH₂, —CONHCH₃, —CH₂CONHCH₃, —CON(CH₃)₂, and —CH₂CON(CH₃)₂;    -   x) —(CR^(102a)R^(102b))_(a)N(R¹⁰¹) C(O)R¹⁰¹; for example,        —NHCOCH₃, —CH₂NHCOCH₃, —NHCOCH₂CH₃, and —CH₂NHCOCH₂CH₃;    -   xi) —(CR^(102a)R^(102b))_(a)N(R¹⁰¹)C(O)R¹⁰¹; for example,        —NHCO₂CH₃, —CH₂NHCO₂CH₃, —NHCO₂CH₂CH₃, and —CH₂NHCO₂CH₂CH₃;    -   xii) —(CR^(102a)R^(102b))_(a)N(R¹⁰¹)₂; for example, —NH₂,        —CH₂NH₂, —NHCH₃, —CH₂NHCH₃, —N(CH₃)₂, and —CH₂N(CH₃)₂;    -   xiii) halogen; —F, —Cl, —Br, and —I;    -   xiv) —(CR^(102a)R^(102b))_(a)CN;    -   xv) (CR^(102a)R^(102b))_(a)NO₂;    -   xvi) —(CH_(j′)X_(k′))_(a)CH_(j)X_(k); wherein X is halogen, the        index j is an integer from 0 to 2, j+k=3; the index j′ is an        integer from 0 to 2, j′+k′=2; for example, —CH₂F, —CHF₂,        —CH₂CH₂F, —CH₂CHF₂, —CF₃, —CCl₃, or —CBr₃;    -   xvii) (CR^(102a)R^(102b))_(a)SR¹⁰¹; —SH, —CH₂SH, —SCH₃,        —CH₂SCH₃, —SC₆H₅, and —CH₂SC₆H₅;    -   xviii) —(CR^(102a)R^(102b))_(a)SO₂R¹⁰¹; for example, —SO₂H,        —CH₂SO₂H, —SO₂CH₃, —CH₂SO₂CH₃, —SO₂C₆H₅, and —CH₂SO₂C₆H₅; and    -   xix) —(CR^(102a)R^(102b))_(a)SO₃R¹⁰¹; for example, —SO₃H,        —CH₂SO₃H, —SO₃CH₃, —CH₂SO₃CH₃, —SO₃C₆H₅, and —CH₂SO₃C₆H₅;        wherein each R¹⁰¹ is independently hydrogen, substituted or        unsubstituted C₁-C₆ linear, C₃-C₆ branched, or C₃-C₆ cyclic        alkyl, phenyl, benzyl, heterocyclic, or heteroaryl; or two R¹⁰¹        units can be taken together to form a ring comprising 3-7 atoms;        R^(102a) and R^(102b) are each independently hydrogen or C₁-C₄        linear or C₃-C₄ branched alkyl; the index “a” is from 0 to 4.

The substitutions for hydrogen defined herein above, for example,substituted C₁-C₁₂ linear, C₃-C₁₂ branched, or C₃-C₁₂ cyclic alkyl,alkenyl, and alkynyl, substituted C₆ or C₁₀ aryl, substituted C₇ or C₁₁alkylenearyl, substituted C₁-C₉ heterocyclic rings, substituted C₁-C₉heteroaryl rings, and R¹⁰¹, can be optionally substituted by one or moreof the following substitutions for hydrogen:

-   -   i) C₁-C₁₂ linear, C₃-C₁₂ branched, or C₃-C₁₂ cyclic alkyl,        alkenyl, and alkynyl; methyl (C₁), ethyl (C₂), ethenyl (C₂),        ethynyl (C₂), n-propyl (C₃), iso-propyl (C₃), cyclopropyl (C₃),        3-propenyl (C₃), 1-propenyl (also 2-methylethenyl) (C₃),        isopropenyl (also 2-methylethen-2-yl) (C₃), prop-2-ynyl (also        propargyl) (C₃), propyn-1-yl (C₃), n-butyl (C₄), sec-butyl (C₄),        iso-butyl (C₄), tert-butyl (C₄), cyclobutyl (C₄), buten-4-yl        (C₄), cyclopentyl (C₅), cyclohexyl (C₆);    -   ii) C₆ or C₁₀ aryl; for example, phenyl, naphthyl (also referred        to herein as naphthylen-1-yl (C₁₀) or naphthylen-2-yl (C₁₀));    -   iii) C₇ or C₁₁ alkylenearyl; for example, benzyl, 2-phenylethyl,        naphthylen-2-ylmethyl;    -   iv) C₁-C₉ heterocyclic rings; as described herein below;    -   v) C₁-C₉ heteroaryl rings; as described herein below;    -   vi) —(CR^(202a)R^(202b))_(b)OR²⁰¹; for example, —OH, —CH₂OH,        —OCH₃, —CH₂OCH₃, —OCH₂CH₃, —CH₂OCH₂CH₃, —OCH₂CH₂CH₃, and        —CH₂OCH₂CH₂CH₃;    -   vii) —(CR^(202a)R^(202b))_(b)C(O)R²⁰¹; for example, —COCH₃,        —CH₂COCH₃, —COCH₂CH₃, —CH₂COCH₂CH₃, —COCH₂CH₂CH₃, and        CH₂COCH₂CH₂CH₃;    -   viii) —(CR^(202a)R^(202b))_(b)C(O)OR²⁰¹; for example, —CO₂CH₃,        —CH₂CO₂CH₃, —CO₂CH₂CH₃, —CH₂CO₂CH₂CH₃, —CO₂CH₂CH₂CH₃, and        —CH₂CO₂CH₂CH₂CH₃;    -   ix) —(CR^(202a)R^(202b))_(b)C(O)N(R²⁰¹)₂; for example, —CONH₂,        —CH₂CONH₂, —CONHCH₃, —CH₂CONHCH₃, —CON(CH₃)₂, and —CH₂CON(CH₃)₂;    -   x) —(CR^(202a)R^(202b))_(b)N(R²⁰¹)C(O)R²⁰¹; for example,        —NHCOCH₃, CH₂NHCOCH₃, —NHCOCH₂CH₃, and —CH₂NHCOCH₂CH₃;    -   xi) —(CR^(202a)R^(202b))_(b)N(R²⁰¹)C(O)₂R²⁰¹; for example,        NHCO₂CH₃, CH₂NHCO₂CH₃, NHCO₂CH₂CH₃, and CH₂NHCO₂CH₂CH₃;    -   xii) (CR^(202a)R²⁰²)_(b)N(R²⁰¹)₂; for example, NH₂, CH₂NH₂,        NHCH₃, CH₂NHCH₃, N(CH₃)₂, and CH₂N(CH₃)₂;    -   xiii) halogen; F, Cl, Br, and I;    -   xiv) —(CR^(202a)R^(202b))_(b)CN;    -   xv) —(CR^(202a)R^(202b))_(b)NO₂;    -   xvi) —(CH_(j′)X_(k′))_(a)CH_(j)X_(k); wherein X is halogen, the        index j is an integer from 0 to 2, j+k=3; the index j′ is an        integer from 0 to 2, j′+k′=2; for example, —CH₂F, CHF₂, CH₂CH₂F,        CH₂CHF₂, CF₃, CCl₃, or CBr₃;    -   xvii) —(CR^(202a)R²⁰²)_(b)SR²⁰¹; SH, CH₂SH, SCH₃, CH₂SCH₃,        SC₆H₅, and CH₂SC₆H₅;    -   xviii) —(CR^(202a)R^(202b))_(b)SO₂R²⁰¹; for example, SO₂H,        CH₂SO₂H, SO₂CH₃, —CH₂SO₂CH₃, SO₂C₆H₅, and CH₂SO₂C₆H₅; and    -   xix) —(CR^(202a)R^(202b))_(b)SO₃R²⁰¹; for example, SO₃H,        CH₂SO₃H, SO₃CH₃, —CH₂SO₃CH₃, SO₃C₆H₅, and CH₂SO₃C₆H₅;        wherein each R²⁰¹ is independently hydrogen, C₁-C₆ linear, C₃-C₆        branched, or C₃-C₆ cyclic alkyl, phenyl, benzyl, heterocyclic,        or heteroaryl; or two R²⁰¹ units can be taken together to form a        ring comprising 3-7 atoms; R^(202a) and R^(202b) are each        independently hydrogen or C₁-C₄ linear or C₃-C₄ branched alkyl;        the index “b” is from 0 to 4.

For the purposes of the present disclosure the terms “compound,”“analog,” and “composition of matter” stand equally well for each otherand are used interchangeably throughout the specification. The disclosedcompounds include all enantiomeric forms, diastereomeric forms, salts,and the like.

The compounds disclosed herein include all salt forms, for example,salts of both basic groups, inter alia, amines, as well as salts ofacidic groups, inter alia, carboxylic acids. The following arenon-limiting examples of anions that can form salts with protonatedbasic groups: chloride, bromide, iodide, sulfate, bisulfate, carbonate,bicarbonate, phosphate, formate, acetate, propionate, butyrate,pyruvate, lactate, oxalate, malonate, maleate, succinate, tartrate,fumarate, citrate, and the like. The following are non-limiting examplesof cations that can form salts of acidic groups: ammonium, sodium,lithium, potassium, calcium, magnesium, bismuth, lysine, tromethamine,meglumine and the like.

The disclosed process can be used to prepare compounds having theformula:

wherein R and R¹ are further defined herein.

Compounds having the formula:

wherein L is a linking group defined herein, have been found to exhibitprolyl hydroxylase inhibition (antagonism). Compounds of this formulahave also been found to stabilize hypoxia inducible factor-2 alpha(HIF-2a). It has also been found that esters and amides having theformula:

can hydrolyze in vivo, in vitro and ex vivo to the correspondingcarboxylic acids shown above. As such, these esters and amides arereferred to herein as “prodrugs.”

R Units

R units have the formula:

wherein X is chosen from:

i) OH;

ii) OR³;

iii) NR⁴R⁵; and

iv) —OM¹.

R³ is C₁-C₁₂ linear, C₃-C₁₂ branched or C₃-C₁₂ cyclic alkyl; C₂-C₁₂linear, C₃-C₁₂ branched or C₃-C₁₂ cyclic alkenyl; or C₂-C₁₂ linear,C₃-C₁₂ branched or C₃-C₁₂ cyclic alkynyl, or benzyl.

R⁴ and R⁵ are each independently hydrogen, C₁-C₁₂ linear, C₃-C₁₂branched or C₃-C₁₂ cyclic alkyl; C₂-C₁₂ linear, C₃-C₁₂ branched orC₃-C₁₂ cyclic alkenyl; or C₂-C₁₂ linear, C₃-C₁₂ branched or C₃-C₁₂cyclic alkynyl; benzyl; or R⁴ and R⁵ can be taken together with thenitrogen atom to form a 3 to 10 member ring, wherein the ring canoptionally contain one or more heteroatoms chosen from oxygen (O),nitrogen (N), or sulfur (S). M¹ represents a cation as further describedherein below.

When a ring is formed from R⁴ and R⁵ and the ring contains a ringnitrogen other than the nitrogen atom to which R⁴ and R⁵ are bonded,then the nitrogen atom can have the form —NR⁹— or ═N—, wherein R⁹ can behydrogen or methyl. Non-limiting examples of this embodiment includescompounds having the formula:

In one aspect, X is hydroxyl, —OH.

In a further aspect, X is —OR³. One embodiment of this aspect relates toX units wherein R³ is C₁-C₆ linear alkyl, for example, methyl (C₁),ethyl (C₂), n-propyl (C₃), n-butyl (C₄), n-pentyl (C₅), and n-hexyl(C₆). Non-limiting examples include the methyl ester, the ethyl ester,the n-propyl ester, and the like.

Another embodiment of this aspect relates to X units wherein R³ is C₃-C₆branched alkyl non-limiting examples of which include iso-propyl (C₃),sec-butyl (C₄), iso-butyl (C₄), tert-butyl (C₄), 1-methylbutyl (C₅),2-methylbutyl (C₅), 3-methylbutyl (C₅), and 4-methylpentyl (C₆).

A further embodiment of this aspect relates to X units wherein R³ isC₃-C₆ cyclic alkyl, for example, cyclopropyl (C₃), cyclobutyl (C₄),cyclopentyl (C₁), and cyclohexyl (C₆).

In another aspect, X is —NR⁴R⁵. One embodiment of this aspect relates toX units wherein R⁴ and R⁵ are both hydrogen; —NH₂.

A further embodiment of this aspect relates to X units wherein R⁴ and R⁵are independently chosen from hydrogen, C₁-C₄ linear alkyl, C₃-C₄branched alkyl, or C₃-C₄ cyclic alkyl, for example, methyl (C₁), ethyl(C₂), n-propyl (C₃), iso-propyl (C₃), n-butyl (C₄), sec-butyl (C₄),iso-butyl (C₄), and tert-butyl (C₄). Non-limiting examples of thisembodiment include —NH₂, —NHCH₃, —N(CH₃)₂, —NHC₂H₅, —N(C₂H₅)₂, and—N(CH₃)(C₂H₅).

L is a linking unit having the formula —(CR^(7a)R^(7b))— wherein R^(7a)and R^(7b) can be independently chosen from hydrogen, C₁-C₆ linear,C₃-C₆ branched or C₃-C₆ cyclic alkyl. The index n is an integer from 1to 4.

In one aspect of L units, R^(7a) and R^(7b) are both hydrogen and theindex n is an integer from 1 to 4, i.e., —CH₂— (methylene), —CH₂CH₂—(ethylene), —CH₂CH₂CH₂— (propylene), and —CH₂CH₂CH₂CH₂— (butylene). Oneiteration of L units according to this aspect relates to compoundshaving the formula:

A further aspect of L units relates to L units wherein R^(7a) and R^(7b)are independently chosen from hydrogen, methyl (C₁), ethyl (C₂),n-propyl (C₃), and iso-propyl (C₃) and the index n is an integer from 1to 4. One embodiment of this aspect relates to L units wherein R^(7a) ishydrogen and R^(7b) is chosen from methyl (C₁), ethyl (C₂), n-propyl(C₃), and iso-propyl (C₃), and the index n is an integer from 1 or 3.Non-limiting examples of this embodiment includes —CH(CH₃)—,—CH₂CH(CH₃)—, —CH(CH₃)CH₂—, —CH(CH₃)CH₂CH₂—, CH₂CH(CH₃)CH₂—, and—CH₂CH₂CH(CH₃)—.

A yet further aspect of L units relates to L units wherein R^(7a) andR^(7b) are independently chosen from methyl (C₁), ethyl (C₂), n-propyl(C₃), and iso-propyl (C₃) and the index n is an integer from 1 to 4. Anon-limiting example of this aspect has the formula —C(CH₃)₂—.

In a still further aspect of L units, L units can be derived from thereaction of an amino acid with a 5-aryl or5-heteroaryl-3-hydroxy-2-carboxypyridine as described herein below inthe disclosure of process step D. One embodiment of this aspect of Lrelates to L units wherein R^(7b) is hydrogen and R^(7a) is chosen fromhydrogen, methyl, iso-propyl, iso-butyl, sec-butyl, hydroxymethyl,1-hydroxyethyl, thiomethyl, 2-(methylthio)ethyl, benzyl,(4-hydroxyphenyl)methyl, indol-3-ylmethyl, imidazol-4-ylmethyl,3-gunidinylpropyl, 4-aminobutyl, carboxymethyl, 2-carboxyethyl,acetamide, or R⁸ and R^(7a) can be taken together to form a pyrrolidinylring, for example, when proline is reacted with the 5-aryl or5-heteroaryl-3-hydroxy-2-carboxypyridine.

The index n can be any integer from 1 to 4, for example n can equal 1, ncan equal 2, n can equal 3, and n can equal 4.

R⁸ is hydrogen, methyl (C₁) or ethyl (C₂). In one aspect R⁸ is hydrogen.In a further aspect R⁸ is methyl (C₁). In another aspect R⁸ is ethyl(C₂).

R¹ Units

R¹ units are chosen from:

-   -   i) substituted or unsubstituted C₆ or C₁₀ aryl; and    -   ii) substituted or unsubstituted C₁-C₉ heteroaryl.    -   Non-limiting examples of substitutions for a hydrogen atom on R¹        units, or alternatively an R¹⁰ unit when R¹ is represented by an        A ring, include:    -   i) C₁-C₁₂ linear, C₃-C₁₂ branched, or C₃-C₁₂ cyclic alkyl,        alkenyl, and alkynyl; for example, methyl (C₁), ethyl (C₂),        ethenyl (C₂), ethynyl (C₂), n-propyl (C₃), iso-propyl (C₃),        cyclopropyl (C₃), 3-propenyl (C₃), 1-propenyl (also        2-methylethenyl) (C₃), isopropenyl (also 2-methylethen-2-yl)        (C₃), prop-2-ynyl (also propargyl) (C₃), propyn-1-yl (C₃),        n-butyl (C₄), sec-butyl (C₄), iso-butyl (C₄), tert-butyl (C₄),        cyclobutyl (C₄), buten-4-yl (C₄), cyclopentyl (C₅), cyclohexyl        (C₆);    -   ii) C₆ or C₁₀ aryl; for example, phenyl, naphthyl (also referred        to herein as naphthylen-1-yl (C₁₀) or naphthylen-2-yl (C₁₀));    -   iii) C₇ or C₁₁ alkylenearyl; for example, benzyl, 2-phenylethyl,        naphthylen-2-ylmethyl;    -   iv) C₁-C₉ heterocyclic rings; as described herein below;    -   v) C₁-C₉ heteroaryl rings; as described herein below;    -   vi) —(CR^(102a)R^(102b))_(a)OR¹⁰¹; for example, —OH, —CH₂OH,        —OCH₃, —CH₂OCH₃, —OCH₂CH₃, —CH₂OCH₂CH₃, —OCH₂CH₂CH₃, and        —CH₂OCH₂CH₂CH₃;    -   vii) —(CR^(102a)R^(102b))_(a)C(O)R¹⁰¹; for example, —COCH₃,        —CH₂COCH₃, —COCH₂CH₃, —CH₂COCH₂CH₃, —COCH₂CH₂CH₃, and        —CH₂COCH₂CH₂CH₃;    -   viii) —(CR^(102a)R^(102b))_(a)C(O)OR¹⁰¹; for example, —CO₂CH₃,        —CH₂CO₂CH₃, —CO₂CH₂CH₃, —CH₂CO₂CH₂CH₃, —CO₂CH₂CH₂CH₃, and        —CH₂CO₂CH₂CH₂CH₃;    -   ix) —(CR^(102a)R^(102b))_(a)C(O)N(R¹⁰¹)₂; for example, —CONH₂,        —CH₂CONH₂, —CONHCH₃, —CH₂CONHCH₃, —CON(CH₃)₂, and —CH₂CON(CH₃)₂;    -   x) —(CR^(102a)R^(102b))_(a)N(R¹⁰¹)C(O)R¹⁰¹; for example,        —NHCOCH₃, —CH₂NHCOCH₃, —NHCOCH₂CH₃, and —CH₂NHCOCH₂CH₃;    -   xi) —(CR^(102a)R^(102b))_(a)N(R¹⁰¹)C(O)₂R¹⁰¹; for example,        —NHCO₂CH₃, —CH₂NHCO₂CH₃, —NHCO₂CH₂CH₃, and —CH₂NHCO₂CH₂CH₃;    -   xii) —(CR^(102a)R^(102b))_(a)N(R¹⁰¹)₂; for example, —NH₂,        —CH₂NH₂, —NHCH₃, —CH₂NHCH₃, —N(CH₃)₂, and —CH₂N(CH₃)₂;    -   xiii) halogen; —F, —Cl, —Br, and —I;    -   xiv) —(CR^(102a)R^(102b))_(a)CN;    -   xv) —(CR^(102a)R^(102b))_(a)NO₂;    -   xvi) —(CH_(j′)X_(k′))_(a)CH_(j)X_(k); wherein X is halogen, the        index j is an integer from 0 to 2, j+k=3; the index j′ is an        integer from 0 to 2, j′+k′=2; for example, —CH₂F, —CHF₂, —CF₃,        —CCl₃, or —CBr₃;    -   xvii) —(CR^(102a)R^(102b))_(a)SR¹⁰¹; —SH, —CH₂SH, —SCH₃,        —CH₂SCH₃, —SC₆H₅, and CH₂SC₆H₅;    -   xviii) —(CR^(102a)R^(102b))_(a)SO₂R¹⁰¹; for example, —SO₂H,        —CH₂SO₂H, —SO₂CH₃, —CH₂SO₂CH₃, —SO₂C₆H₅, and —CH₂SO₂C₆H₅; and    -   xix) —(CR^(102a)R^(102b))_(a)SO₃R¹⁰¹; for example, —SO₃H,        —CH₂SO₃H, —SO₃CH₃, —CH₂SO₃CH₃, —SO₃C₆H₅, and —CH₂SO₃C₆H₅; or    -   xx) two substitutions for hydrogen can be taken together to form        a substituted or unsubstituted C₂-C₈ heterocyclic ring, wherein        the ring substitution can be one or more of the substitutions        defined in (i) to (xix) herein above and the ring can comprise        one or more heteroatoms chosen from oxygen (O) sulfur (S), or        nitrogen (N);        wherein each R¹⁰¹ is independently hydrogen, substituted or        unsubstituted C₁-C₆ linear, C₃-C₆ branched, or C₃-C₆ cyclic        alkyl, phenyl, benzyl, heterocyclic, or heteroaryl; or two R¹⁰¹        units can be taken together to form a ring comprising 3-7 atoms;        R^(102a) and R^(102b) are each independently hydrogen or C₁-C₄        linear or C₃-C₄ branched alkyl; the index “a” is from 0 to 4.

Stated in another way, the disclosed process relates to the formation ofcompounds having the formula:

wherein the A ring represents R¹ units wherein R¹ can be:

i) substituted or unsubstituted C₆ or C₁₀ aryl; and

ii) substituted or unsubstituted C₁-C₉ heteroaryl;

wherein the substitutes for hydrogen atoms on the A ring are one or moreR¹⁰ units that are independently chosen and further described herein.

One aspect of R¹ relates to substituted or unsubstituted C₆ aryl, i.e.,substituted or unsubstituted phenyl. A first embodiment of this aspectrelates to R¹ equal to phenyl, for example, compounds having theformula:

A further aspect of R¹ relates to R¹ units that are substituted phenylhaving the formula:

wherein R¹⁰ represents from 1 to 5 independently chosen substitutionsfor hydrogen; or two R¹⁰ units can be taken together to form asubstituted or unsubstituted C₄-C₈ cycloalkyl ring, a substituted orunsubstituted C₆ aryl ring (phenyl), a substituted or unsubstitutedC₂-C₈ heterocyclic ring, or a substituted or unsubstituted C₃ to C₅heteroaryl ring, wherein the heterocyclic and heteroaryl rings compriseone or more hetero atoms independently chosen from oxygen (O), nitrogen(N), or sulfur (S).

One embodiment of this aspect of R¹ units relates to compoundscomprising substitutions on R¹ of one or more units independently chosenfrom:

i) C₁-C₁₂ linear, C₃-C₁₂ branched or C₃-C₁₂ cyclic alkyl;

ii) C₁-C₁₂ linear, C₃-C₁₂ branched or C₃-C₁₂ cyclic alkoxy; and

iii) halogen: —F, —Cl, —Br, and —I.

One iteration of this embodiment relates to compounds comprising one ormore R¹⁰ units that are halogen, thereby forming the followingnon-limiting examples of R¹ units: 2-fluorophenyl, 3-fluorophenyl,4-fluorophenyl, 2,3-difluorophenyl, 3,4-difluorophenyl,3,5-difluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl,2,3-dichlorophenyl, 3,4-dichlorophenyl, 2-bromophenyl, 3-bromophenyl,4-bromophenyl, 3,5-dichlorophenyl, 2,3,4-trifluorophenyl,2,3,5-trifluorophenyl, 2,3,6-trifluorophenyl, 2,4,5-trifluorophenyl,2,4,6-trifluorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl,2,6-dichlorophenyl, 3,4-dichlorophenyl, 2,3,4-trichlorophenyl,2,3,5-trichlorophenyl, 2,3,6-trichlorophenyl, 2,4,5-trichlorophenyl,3,4,5-trichlorophenyl, and 2,4,6-trichlorophenyl.

A further iteration relates to compounds comprising one or more R¹⁰units that are C₁-C₄ linear, C₃-C₄ branched or C₃-C₄ cyclic alkyl,thereby forming the following non-limiting examples of R¹ units:2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2,3-dimethylphenyl,2,4-dimethylphenyl, 2,5-dimethylphenyl, 2,6-dimethylphenyl,3,4-dimethylphenyl, 2,3,4-trimethylphenyl, 2,3,5-trimethylphenyl,2,3,6-trimethylphenyl, 2,4,5-trimethylphenyl, 2,4,6-trimethylphenyl,2-ethylphenyl, 3-ethylphenyl, 4-ethylphenyl, 2,3-diethylphenyl,2,4-diethylphenyl, 2,5-diethylphenyl, 2,6-diethylphenyl,3,4-diethylphenyl, 2,3,4-triethylphenyl, 2,3,5-triethylphenyl,2,3,6-triethylphenyl, 2,4,5-triethylphenyl, 2,4,6-triethylphenyl,2-isopropylphenyl, 3-isopropylphenyl, and 4-isopropylphenyl.

Another iteration relates to compounds comprising one or more R¹⁰ unitsthat are C₁-C₄ linear, C₃-C₄ branched or C₃-C₄ cyclic alkoxy, therebyforming the following non-limiting examples of R¹ units:2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2,3-dimethoxyphenyl,2,4-dimethoxyphenyl, 2,5-dimethoxyphenyl, 2,6-dimethoxyphenyl,3,4-dimethoxyphenyl, 2,3,4-trimethoxyphenyl, 2,3,5-trimethoxyphenyl,2,3,6-trimethoxyphenyl, 2,4,5-trimethoxyphenyl, 2,4,6-trimethoxyphenyl,2-ethoxyphenyl, 3-ethoxyphenyl, 4-ethoxyphenyl, 2,3-diethoxyphenyl,2,4-diethoxyphenyl, 2,5-diethoxyphenyl, 2,6-diethoxyphenyl,3,4-diethoxyphenyl, 2,3,4-triethoxyphenyl, 2,3,5-triethoxyphenyl,2,3,6-triethoxyphenyl, 2,4,5-triethoxyphenyl, 2,4,6-triethoxyphenyl,2-isopropoxyphenyl, 3-isopropoxyphenyl, and 4-isopropoxyphenyl.

A yet still further iteration relates to compounds comprising one ormore R¹⁰ units that comprise at least one of each substitution chosenfrom C₁-C₄ linear or halogen, thereby forming the following non-limitingexamples of R¹ units: 2-chloro-3-methylphenyl, 2-chloro-4-methylphenyl,2-chloro-5-methylphenyl, 2-chloro-6-methylphenyl,3-chloro-2-methylphenyl, 3-chloro-4-methylphenyl,3-chloro-5-methylphenyl, 3-chloro-6-methyl-phenyl,2-fluoro-3-methylphenyl, 2-fluoro-4-methylphenyl,2-fluoro-5-methylphenyl, 2-fluoro-6-methylphenyl,3-fluoro-2-methylphenyl, 3-fluoro-4-methylphenyl,3-fluoro-5-methylphenyl, and 3-fluoro-6-methylphenyl.

One embodiment of this aspect of R¹ units relates to compoundscomprising one or more R¹⁰ units independently chosen from:

-   -   i) —(CR^(102a)R^(102b))_(a)CN;    -   ii) —(CR^(102a)R^(102b))_(a)NO₂; and    -   iii) —(CH_(j )X_(k′))_(a)CH_(j)X_(k); wherein X is halogen, the        index j is an integer from 0 to 2, j+k=3; the index j′ is an        integer from 0 to 2, j′+k′=2.

On iteration of this embodiment relates to compounds comprising one ormore R¹⁰ units that are —(CH₂)_(a)CN, wherein the index a is 0 or 1,thereby forming the following non-limiting examples of R¹ units:2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 2-(cyanomethyl)phenyl,3-(cyanomethyl)phenyl, 4-(cyanomethyl)phenyl, 2,3-dicyanophenyl,3,4-dicyanophenyl, and 3,5-dicyanophenyl.

Another iteration of this embodiment relates to compounds comprising oneor more R¹⁰ units that are —(CH₂)_(a)NO₂, wherein the index a is 0 or 1,thereby forming the following non-limiting examples of R¹ units:2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 2-(nitromethyl)phenyl,3-(nitromethyl)phenyl, 4-(nitromethyl)phenyl, 2,3-dinitrophenyl,3,4-dinitrophenyl, and 3,5-dinitrophenyl.

A further iteration of this embodiment relates to compounds comprisingone or more R¹⁰ units that are —CH_(j)X_(k); wherein X is halogen, theindex j is an integer from 0 to 2, j+k=3, wherein the index a is 0 or 1,thereby forming the following non-limiting examples of R¹ units: —CH₂F,—CH₂CH₂F, —CHF₂, —CH₂CHF₂, —CF₃, —CH₂CF₃, —CHFCH₂F, —CF₂CHF₂, —CF₂CF₃,—CH₂Cl, —CH₂CH₂Cl, —CHCl₂, —CH₂CHCl₂, —CCl₃, —CH₂CCl₃, —CHClCH₂Cl,—CCl₂CHCl₂, and —CCl₂CCl₃.

One embodiment of this aspect of R¹ units relates to compoundscomprising one or more R¹⁰ units independently chosen from:

i) —(CR^(102a)R^(102b))_(a)N(R¹⁰¹)₂;

ii) —(CR^(102a)R^(102b))_(a)C(O)N(R¹⁰¹)₂; and

iii) —(CR^(102a)R^(102b))_(a)N(R¹⁰¹)C(O)₂R¹⁰¹.

One iteration of this embodiment relates to compounds comprising one ormore R¹⁰ units that are —(CR^(102a)R^(102b))_(a)N(R¹⁰¹)₂, wherein theindex a is 0 or 1, thereby forming the following non-limiting examplesof R¹ units: 2-aminophenyl, 3-aminophenyl, 4-aminophenyl,2,3-diaminophenyl, 3,4-diaminophenyl, 3,5-diaminophenyl,2-methylaminophenyl, 3-methylaminophenyl, 4-methylaminophenyl,2,3-(dimethylamino)phenyl, 3,4-(dimethylamino)phenyl,3,5-(dimethylamino)phenyl, 2,3,4-triaminophenyl, 2,3,5-triaminophenyl,2,3,6-triaminophenyl, 2,4,5-triaminophenyl, 2,4,6-triaminophenyl,2,4-(dimethylamino)phenyl, 2,5-(dimethylamino)phenyl,2,6-(dimethylamino)phenyl, 3,4-(dimethylamino)phenyl,2,3,4-(dimethylamino)phenyl, 2,3,5-(dimethylamino)phenyl,2,3,6-(dimethylamino)phenyl, 2,4,5-(dimethylamino)phenyl,3,4,5-(dimethylamino)phenyl, and 2,4,6-(dimethylamino)phenyl.

Another iteration of this embodiment relates to compounds comprising oneor more R¹⁰ units that are —(CR^(102a)R^(102b))_(a)C(O)N(R¹⁰¹)₂, whereinR¹⁰¹ is chosen from hydrogen, C₁-C₆ linear, C₃-C₆ branched alkyl orC₃-C₆ cyclic alkyl, and the index a is 0 or 1, thereby forming thefollowing non-limiting examples of R¹ units: —C(O)NH₂, —C(O)NHCH₃,—CH₂C(O)NHCH₃, —C(O)N(CH₃)₂, —CH₂C(O)N(CH₃)₂, —C(O)NHCH₂CH₃,—CH₂C(O)NHCH₂CH₃, —C(O)N(CH₂CH₃)₂, —CH₂C(O)N(CH₂CH₃)₂, —C(O)NHCH(CH₃)₂,—CH₂C(O)NHCH(CH₃)₂, —C(O)N[CH(CH₃)₂]₂, and —CH₂C(O)N[CH(CH₃)₂]₂.

Another iteration of this embodiment relates to compounds comprising oneor more R¹⁰ units that are —(CR^(102a)R^(102b))_(a)C(O)N(R¹⁰¹)₂, whereintwo R¹⁰¹ units are taken together to form a ring having from 3 to 7atoms and the index a is 0 or 1, thereby forming R¹ units having, forexample, the formulae:

A further iteration of this embodiment relates to compounds comprisingone or more R¹⁰ units that are —(CR^(102a)R^(102b))_(a)N(R¹⁰¹)C(O)₂R¹⁰¹;wherein R¹⁰¹ is chosen from hydrogen, C₁-C₆ linear, C₃-C₆ branched alkylor C₃-C₆ cyclic alkyl, and the index a is 0 or 1, thereby forming thefollowing non-limiting examples of R¹ units: —NHC(O)CH₃, —CH₂NHC(O)CH₃,—NHC(O)CH₂CH₃, —CH₂NHC(O)CH₂CH₃, —NHC(O)CH₂CH₂CH₃, —CH₂NHC(O)CH₂CH₂CH₃,—NHC(O)(cyclopropyl), and —CH₂NHC(OX)(cyclopropyl).

Another aspect of R¹ relates to R¹ units that are substituted orunsubstituted C₁-C₉ heteroaryl. One embodiment of this aspect relates toR¹ equal to C₁-C₉ heteroaryl, for example, compounds having the formula:

wherein ring A represent a C₁-C₉ heteroaryl unit non-limiting examplesof which include: 1,2,3,4-tetrazolyl (C₁), [1,2,3]triazolyl (C₂),[1,2,4]triazolyl (C₂), [1,2,4]oxadiazolyl (C₂), [1,3,4]oxadiazolyl (C₂),[1,2,4]thiadiazolyl (C₂), [1,3,4]thiadiazolyl (C₂), isothiazolyl (C₃),thiazolyl (C₃), imidazolyl (C₃), oxazolyl (C₃), isoxazolyl (C₃),pyrazolyl (C₃), pyrrolyl (C₄), furanyl (C₄), thiophenyl (C₄), triazinyl(C₃), pyrimidinyl (C₄), pyrazinyl (C₄), pyridazinyl (C₄), pyridinyl(C₅), purinyl (C₅), xanthinyl (C₅), hypoxanthinyl (C₅), benzimidazolyl(C₇), indolyl (C₅), quinazolinyl (C₅), quinolinyl (C₉), andisoquinolinyl (C₉).

In a further embodiment of this aspect the C₁-C₉ heteroaryl unit can bebonded to the core pyridine ring at any suitable position, non-limitingexamples of which include:

Another embodiment of this aspect relates to R¹ units equal tosubstituted C₁-C₉ heteroaryl, for example, compounds having the formula:

wherein ring A represent a C₁-C₉ heteroaryl unit non-limiting examplesof which include: 1,2,3,4-tetrazolyl (C₁), [1,2,3]triazolyl (C₂),[1,2,4]triazolyl (C₂), [1,2,4]oxadiazolyl (C₂), [1,3,4]oxadiazolyl (C₂),[1,2,4]thiadiazolyl (C₂), [1,3,4]thiadiazolyl (C₂), isothiazolyl (C₃),thiazolyl (C₃), imidazolyl (C₃), oxazolyl (C₃), isoxazolyl (C₃),pyrazolyl (C₃), pyrrolyl (C₄), furanyl (C₄), thiophenyl (C₄), triazinyl(C₃), pyrimidinyl (C₄), pyrazinyl (C₄), pyridazinyl (C₄), pyridinyl(C₅), purinyl (C₅), xanthinyl (C₅), hypoxanthinyl (C₅), benzimidazolyl(C₇), indolyl (C₅), quinazolinyl (C₅), quinolinyl (C₉), andisoquinolinyl (C₉).

Non-limiting examples of substitutions for a hydrogen atom on R¹C₁-C₉heteroaryl units include:

-   -   i) C₁-C₁₂ linear, C₃-C₁₂ branched, or C₃-C₁₂ cyclic alkyl,        alkenyl, and alkynyl; methyl (C), ethyl (C₂), ethenyl (C₂),        ethynyl (C₂), n-propyl (C₃), iso-propyl (C₃), cyclopropyl (C₃),        3-propenyl (C₃), 1-propenyl (also 2-methylethenyl) (C₃),        isopropenyl (also 2-methylethen-2-yl) (C₃), prop-2-ynyl (also        propargyl) (C₃), propyn-1-yl (C₃), n-butyl (C₄), sec-butyl (C₄),        iso-butyl (C₄), tert-butyl (C₄), cyclobutyl (C₄), buten-4-yl        (C₄), cyclopentyl (C₅), cyclohexyl (C₆);    -   ii) C₆ or C₁₀ aryl; for example, phenyl, naphthyl (also referred        to herein as naphthylen-1-yl (C₁₀) or naphthylen-2-yl (C₁₀));    -   iii) C₇ or C₁₁ alkylenearyl; for example, benzyl, 2-phenylethyl,        naphthylen-2-ylmethyl;    -   iv) C₁-C₉ heterocyclic rings; as described herein below;    -   v) C₁-C₉ heteroaryl rings; as described herein below;    -   vi) —(CR^(102a)R^(102b))_(a)OR¹⁰¹; for example, —OH, —CH₂OH,        —OCH₃, —CH₂OCH₃, —OCH₂CH₃, —CH₂OCH₂CH₃, —OCH₂CH₂CH₃, and        —CH₂OCH₂CH₂CH₃;    -   vii) —(CR^(102a)R^(102b))_(a)C(O)R¹⁰¹; for example, —COCH₃,        —CH₂COCH₃, —COCH₂CH₃, —CH₂COCH₂CH₃, —COCH₂CH₂CH₃, and        —CH₂COCH₂CH₂CH₃;    -   viii) —(CR^(102a)R^(102b))_(a)C(O)OR¹⁰¹; for example, —CO₂CH₃,        —CH₂CO₂CH₃, —CO₂CH₂CH₃, —CH₂CO₂CH₂CH₃, —CO₂CH₂CH₂CH₃, and        —CH₂CO₂CH₂CH₂CH₃;    -   ix) —(CR^(102a)R^(102b))_(a)C(O)N(R¹⁰¹)₂; for example, —CONH₂,        —CH₂CONH₂, —CONHCH₃, —CH₂CONHCH₃, —CON(CH₃)₂, and —CH₂CON(CH₃)₂;    -   x) —(CR^(102a)R^(102b))_(a)N(R¹⁰¹)C(O)R¹⁰¹; for example,        —NHCOCH₃, —CH₂NHCOCH₃, —NHCOCH₂CH₃, and —CH₂NHCOCH₂CH₃;    -   xi) —(CR^(102a)R^(102b))_(a)N(R¹⁰¹)C(O)₂R¹⁰¹; for example,        —NHCO₂CH₃, —CH₂NHCO₂CH₃, —NHCO₂CH₂CH₃, and —CH₂NHCO₂CH₂CH₃;    -   xii) —(CR^(102a)R^(102b))_(a)N(R¹⁰¹)₂; for example, —NH₂,        —CH₂NH₂, —NHCH₃, —CH₂NHCH₃, —N(CH₃)₂, and —CH₂N(CH₃)₂;    -   xiii) halogen; —F, —Cl, —Br, and —I;    -   xiv) —(CR^(102a)R^(102b))_(a)CN;    -   xv) —(CR^(102a)R^(102b))_(a)NO₂;    -   xvi) —(CH_(j′)X_(k′))_(a)CH_(j)X_(k); wherein X is halogen, the        index j is an integer from 0 to 2, j+k=3; the index j′ is an        integer from 0 to 2, j′+k′=2; for example, —CH₂F, —CHF₂, —CF₃,        —CCl₃, or —CBr₃;    -   xvii) —(CR^(102a)R^(102b))_(a)SR¹⁰¹; —SH, —CH₂SH, —SCH₃,        —CH₂SCH₃, —SC₆H₅, and CH₂SC₆H₅;    -   xviii) —(CR^(102a)R^(102b))_(a)SO₂R¹⁰¹; for example, —SO₂H,        —CH₂SO₂H, —SO₂CH₃, CH₂SO₂CH₃, —SO₂C₆H₅, and —CH₂SO₂C₆H₅; and    -   xix) —(CR^(102a)R^(102b))_(a)SO₃R¹⁰¹; for example, —SO₃H,        —CH₂SO₃H, —SO₃CH₃, —CH₂SO₃CH₃, —SO₃C₆H₅, and —CH₂SO₃C₆H₅;        wherein each R¹⁰¹ is independently hydrogen, substituted or        unsubstituted C₁-C₆ linear, C₃-C₆ branched, or C₃-C₆ cyclic        alkyl, phenyl, benzyl, heterocyclic, or heteroaryl; or two R¹⁰¹        units can be taken together to form a ring comprising 3-7 atoms;        R^(102a) and R^(102b) are each independently hydrogen or C₁-C₄        linear or C₃-C₄ branched alkyl; the index “a” is from 0 to 4.

Non-limiting examples of substituted C₅-C₉ R¹ heteroaryl units include2-methylthiazol-4-yl, 2-ethylthiazol-4-yl, 2-(n-propyl)thiazol-4-yl,2-(iso-propyl)thiazol-4-yl, 4,5-dimethylthiazol-2-yl,4-ethyl-5-methylthiazol-2-yl, 4-methyl-5-ethylthiazol-2-yl,4,5-diethylthiazol-2-yl, 3-methyl-1,2,4-oxadiazol-5-yl,4,5-dimethylimidazol-2-yl, 4-ethyl-5-methylimidazol-2-yl,4-methyl-5-ethylimidazol-2-yl, 4,5-diethylimidazol-2-yl,2,5-dimethylthiazol-4-yl, 2,4-dimethylthiazol-5-yl,3-methyl-1,2,4-oxadiazol-5-yl, 4,5-dimethyloxazol-2-yl,4-ethyl-5-methyloxazol-2-yl, 4-methyl-5-ethyloxazol-2-yl,4,5-diethyloxazol-2-yl, 2-methyloxazol-4-yl, 2-ethyloxazol-4-yl,2-(n-propyl)oxazol-4-yl, 2-(iso-propyl)oxazol-4-yl, 2-methyloxazol-4-yl,2-ethyloxazol-4-yl, 2-(n-propyl)oxazol-4-yl, 2-(iso-propyl)oxazol-4-yl,5-methyl[1,2,4]oxadiazol-3-yl, 5-ethyl[1,2,4]-oxadiazol-3-yl,5-propyl[1,2,4]oxadiazol-3-yl, 5-cyclopropyl[1,2,4]oxadiazol-3-yl,3-methyl[1,2,4]oxadiazol-5-yl, 3-ethyl[1,2,4]oxadiazol-5-yl,3-(n-propyl)[1,2,4]oxadiazol-5-yl, 3-(iso-propyl)[1,2,4]oxadiazol-5-yl,2,5-dimethylthiazol-4-yl, 2,4-dimethylthiazol-5-yl, 4-ethylthiazol-2-yl,3-methyl-1,2,4-oxadiazol-5-yl, 4,5-dimethylpyrimidin-2-yl,4,5-diethylpyrimidin-2-yl, 4-methyl-5-ethyl-pyrimidin-2-yl,4-ethyl-5-methyl-pyrimidin-2-yl, 4-(thiophen-2-yl)pyrimidin-2-yl,5-(thiophen-2-yl)pyrimidin-2-yl, 4-(thiophen-3-yl)pyrimidin-2-yl, and5-(thiophen-2-yl)pyrimidin-3-yl.

Non-limiting examples of substituted C₂-C₄ 5-member heteroaryl ringsinclude:

A yet further aspect of R¹ units relates to rings comprising two R¹⁰substitutions for hydrogen that are taken together to form a substitutedor unsubstituted C₂-C₈ heterocyclic ring. One embodiment of this aspectrelates to R¹ units wherein two R¹⁰ units are taken together to form asubstituted or unsubstituted C₇-C₉ heterocyclic R¹ ring system whereinthe heterocyclic ring formed by the two R¹⁰ substitutions contains oneor more nitrogen atoms. Non-limiting iterations of this embodimentinclude R¹ units having the formulae:

Another embodiment of this aspect relates to R¹ units wherein two R¹⁰units are taken together to form a substituted or unsubstituted C₇-C₉heterocyclic R¹ ring system wherein the heterocyclic ring formed by thetwo R¹⁰ substitutions contains one or more oxygen atoms. Non-limitingiterations of this embodiment include R¹ units having the formulae:

R² Units

R² units are chosen from C₁-C₁₂ linear alkyl or C₃-C₁₂ branched alkyl.In one embodiment R² can represent hydrogen. In another embodiment, R²is C₁-C₄ linear alkyl. Non-limiting examples include methyl, ethyl andn-propyl. In one example, R² is methyl.

R² units relate to the alkoxide unit having the formula:

^(⊖)OR²

that is used in the process disclosed herein. As it relates to thealkoxide, the alkoxide can be derived from any suitable source, i.e.,sodium methoxide, lithium ethoxide, and the like which the formulatorcan choose.

A further aspect of the present disclosure relates to a process forpreparing intermediates having the formula:

wherein R¹ is the same as defined herein above. This aspect alsoincludes salts of acids, for example, compounds having the formula:

wherein M is a salt forming cation and N represents the cationic chargeon M and the number of corresponding anionic units of the disclosedintermediates. The M units can comprise in one embodiment inorganiccations, inter alia, ammonium, sodium, lithium, potassium, calcium,magnesium, bismuth, and the like. In another embodiment, M units cancomprise organic cation forming units, inter alia, lysine, ornithine,glycine, alanine, or other amino acids, basic organic compounds, interalia, methylamine, dimethylamine, trimethylamine, and the like.

Another aspect of the present disclosure relates to a process forpreparing intermediates having the formula:

wherein W is a salt forming anion and Y represents the anionic charge onW and the number of corresponding number of the disclosed intermediatesin this salt form. The W units can comprise in one embodiment inorganicanions, inter alia, chloride, bromide, iodide, sulfate, bisulfate,carbonate, bicarbonate, phosphate, and the like. In another embodiment,W units can comprise organic anion forming units, inter alia, formate,acetate, propionate, butyrate, pyruvate, lactate, oxalate, malonate,maleate, succinate, tartrate, fumarate, citrate, and the like.

In one aspect, the disclosed prolyl hydroxylase inhibitors can beisolated as a pharmaceutically acceptable salt having the formula:

wherein M is a salt forming cation and N represents the cationic chargeon M and the number of corresponding anionic units present in the salt.

One aspect of the disclosed salts relates to prolyl hydroxylaseinhibitors in the form of the mono-valent salt having the formula:

wherein M represents an inorganic or organic cation. Non-limitingexamples of mono-valent cations include sodium, lithium, potassium,ammonium, silver, organic cations having the formula HN⁺R^(a)R^(b)R^(c)wherein R^(a), R^(b) and R are each independently:

-   -   i) hydrogen;    -   ii) substituted or unsubstituted C₁-C₁₂ linear, C₃-C₁₂ branched,        or C₃-C₁₂ cyclic alkyl;    -   iii) substituted or unsubstituted benzyl;        wherein one or more of R^(a), R^(b) and R^(c) can be        independently substituted by one or more units chosen from:    -   i) C₁-C₁₂ linear, C₃-C₁₂ branched, or C₃-C₁₂ cyclic alkoxy;    -   ii) C₁-C₁₂ linear, C₃-C₁₂ branched, or C₃-C₁₂ cyclic haloalkoxy;    -   iii) halogen;    -   iv) hydroxyl;    -   v) thio; or    -   vi) one or more of R^(a), R^(b) and R^(c) can contain one or        more units capable of forming a cation, anion, or zwitterions.

One iteration of this embodiment relates to cations wherein each ofR^(a), R^(b) and R^(c) are hydrogen or C₁-C₁₂ linear alkyl. Non-limitingexamples include methyl ammonium [HN⁺H₂(CH₃)], dimethyl ammonium[HN⁺H(CH₃)₂], trimethyl ammonium [HN⁺(CH₃)₃], ethyl ammonium[HN⁺H₂(CH₂CH₃)], diethyl ammonium [HN⁺H(CH₂CH₃)₂], triethyl ammonium[HN⁺(CH₂CH₃)₃], dimethylethyl ammonium [HN⁺(CH₃)₂(CH₂CH₃)], andmethyldiethyl ammonium [HN⁺(CH₃)(CH₂CH₃)₂].

Another iteration of this embodiment relates to cations wherein one ormore of R^(a), R^(b) and R^(c) are chosen from hydrogen, unsubstitutedC₁-C₂ linear, C₃-C₁₂ branched, or C₃-C₁₂ cyclic alkyl or substitutedC₁-C₁₂ linear, C₃-C₁₂ branched, or C₃-C₁₂ cyclic alkyl. One embodimentrelates to organic cations having one or more C₁-C₁₂ linear, C₃-C₁₂branched, or C₃-C₁₂ cyclic alkyl chains substituted with hydroxy.Non-limiting examples include 2-hydroxyethyl ammonium (cation ofmonoethanolamine, cholinate) [HN⁺H₂(CH₂CH₂OH)], methyl-2-hydroxyethylammonium [H₂N+(CH₃)(CH₂CH₂OH)], di(2-hydroxyethyl) ammonium[H₂N⁺(CH₂CH₂OH)₂], tri(2-hydroxyethyl) ammonium [HN⁺(CH₂CH₂OH)₃], andtris(hydroxymethyl)methyl ammonium (cation oftris(hydroxymethyl)aminomethane) [H₃N+C[(CH₂OH)]₃]. Also included arecations formed from amino sugars, for example, amino sugars having theformula H₂N+(CH₃)[(CHOH)_(n)CH₂OH] wherein n is from 1 to 7. Anon-limiting example of an amino sugar suitable for forming an organiccation is meglumine (1-deoxy-1-methylamino-sorbitol).

A further iteration of this embodiment relates to cations formed fromamino acids. Non-limiting examples include lysine, omithine, arginine,glutamine, and the like.

Another aspect of organic amines suitable for forming salts of thedisclosed stabilizer include amines wherein one or more of R^(a), R^(b)and R^(c) are taken together to form a heterocyclic ring that cancomprise from 3 to 20 atoms and optionally one or more heteroatomschosen from nitrogen, oxygen and sulfur. Non-limiting examples includepiperazine, piperidine, morpholine, thiomorpholine, and the like.

In addition, di-valent cations can be used wherein the salts of theseexamples have the formula:

Non-limiting examples of di-valent cations includes calcium magnesium,barium and the like.

Another example of salts includes the di-anions having the formula:

wherein M is the same as defined herein above.

The importance of the herein disclosed intermediates lies in the factthat the formulator can prepare an admixture comprising a plurality offinal compounds in one step by the choice of reactants in the finalprocess step as described herein. For example, it is known by theartisan that, although two or more analogs can have approximately equalpharmacological activity, other properties such as bioavailability canbe different. Using the disclosed intermediates to form admixtures offinal analogs can provide the formulator with a final composition whichutilizes the disparate pharmacological activities of the molecules toprovide for a constant level of a desired property. For example, oneanalog in the admixture can have immediate bioavailability while asecond or third compound has a slower bioavailability which can providea pharmacologically active composition that has a steady or near steadylevel of drug active in a user.

Process

Disclosed herein is a process for preparing the herein above disclosed[(5-phenyl-3-hydroxypyridine-2-carbonyl)-amino]alkanoic acids and[(5-heteroaryl-3-hydroxypyridine-2-carbonyl)-amino]alkanoic acids. Asdisclosed herein, the 5-phenyl and 5-heteroaryl rings can be substitutedby one or more independently chosen substitutions for hydrogen.

The following is a summary of the steps that comprise the disclosedprocess.

Step A

Step A relates to the condensation of an aryl or heteroaryl borateprecursor, A1, and a 3,5-dihalo-2-cyanopyridine, A2, wherein each Z isindependently chloro or bromo, to form a 5-aryl or5-heteroaryl-3-halo-2-cyanopyridine, A3.

The borate precursor, A1, comprises ring A wherein ring A can be:

A) substituted or unsubstituted C₆ or C₁₀ aryl; and

ii) substituted or unsubstituted C₁-C₉ heteroaryl;

wherein the substitutes for hydrogen atoms on the A ring are one or moreR¹⁰ units that are independently chosen and further described herein. Yis OR², wherein R²⁰ is hydrogen or C₁-C₆ linear, C₃-C₆ branched, orC₃-C₆ cyclic alkyl, or two OR²⁰ units can be taken together to form a5-member to 7-member C₃-C₁₀ cyclic ester, for example, a cyclic esterhaving the formula:

One aspect of borate precursors relates to phenyl boronic acid havingthe formula:

Another aspect of borate precursors relates to substituted boronic acidshaving the formula:

wherein R¹⁰ represents from 1 to 5 substitutions as defined hereinabove. Non-limiting examples of this aspect includes borate precursorshaving the formula:

The 3,5-dihalo-2-cyanopyridine, A2, is chosen from3,5-dichloro-2-cyanopyridine, 3-chloro-5-bromo-2-cyanopyridine,3,5-dibromo-2-cyanopyridine and 3-bromo-5-chloro-2-cyanopyridine.

Step A is conducted in the presence of a catalyst, for example, a Suzukicoupling catalyst. The formulator can choose the catalyst and conditionsthat are compatible with the reagents, i.e., borate precursor and3,5-dihalo-2-cyanopyridine. (See, Suzuki, A. Pure Appl. Chem. 1991, 63,419-422; Suzuki, A., J. Organometallic Chem. 1999, 576, 147-168; Barder,T. E. et al., “Catalysts for Suzuki-Miyaura Coupling Processes: Scopeand Studies of the Effect of Ligand Structure,” J. Am. Chem. Soc. 2005,127, 4685-4696 included herein by reference in their entirety.)

In one embodiment, the catalyst is[1,1′-bis(diphenyphosphino)ferrocene]dichloro-palladium(II)[PdCl₂(dppf)].

Another category of catalysts include ortho-metalated catalysts withalkylphosphine ligands of the general formula[Pd(X)(κ²N,C—C₆H₄CH₂NMe₂)(PR₃)] wherein R is Cy, X is trifluoroacetate,trifluoromethanesufonyl, chloro, or iodo; PR₃ is PCy₂(o-biphenyl), X istrifluoroacetate). Non-limiting examples of this category include[{Pd(μ-TFA)(κ²N,C—C₆H₄CH₂NMe₂)}₂] and[{Pd(TFA)(κ²N,C—C₆H₄CH═N^(i)Pr)}₂].

The catalyst can be preformed, for example, purchased from a chemicalsupplier or the catalyst can be generated in situ. One non-limitingexample of Step A wherein the catalyst is generated in situ includes thefollowing procedure. Pd(OAc)₂ (1.5 mmol %),3,3′-dimethyl-1,1′(2,4-bismethylenemesitylene)(4,4,5,6-tetrahydropyrimidinium)chloride (1.5 mmol %), a borate precursor (1.5 mmol), a3,5-dihalo-2-cyanopyridine (1.0 mmol), K₂CO₃ (2 mmol), water (3 mL)-DMF(3 mL) are added to a small Schlenk tube and the mixture heated at 80°C. for 5 hours. At the conclusion of the reaction, the mixture iscollected, removed by extraction with suitable solvent, and the desiredproduct isolated by methods known to the artisan.

Step A is conducted in the presence of a base. Non-limiting examples ofsuitable bases that can be used in Step A includes LiOH, NaOH, KOH,Ca(OH)₂, Li₂CO₃, Na₂CO₃, K₂CO₃, and CaCO₃. In one embodiment, the baseis K₂CO₃. In another embodiment, the base is Na₂CO₃.

Step A can be optionally conducted in the presence of a solvent.Non-limiting examples of solvents include water, formic acid, aceticacid; alcohols, for example, methanol, ethanol, 2,2,2-trichlorethanol,propanol, isopropanol, butanol, tert-butanol, and the like; ketones, forexample, acetone, methyl ethyl ketone, diethyl ketone, and the like;esters, for example, methyl acetate, ethyl acetate, methyl propionate,ethyl propionate, and the like; ethers, for example, diethyl ether,methyl tert-butyl ether, tetrahydrofuran, dimethoxyethane,bis(2-methoxyethyl) ether (diglyme), 1,4-dioxane, and the like; alkanes,for example, pentane, isopentane, petroleum ether, hexane, mixtures ofhexanes, cyclohexane, heptanes, isoheptane, octane, isooctane, and thelike; halogenated solvents, for example, dichloromethane, chloroform,carbon tetrachloride, 1,1-dichloroethane, 1,1,1-trichloroethane,1,2-dichloroethane, chlorobenzene, and the like; aromatic hydrocarbons,for example, benzene, toluene, 1,2-dimethylbenzene (ortho-xylene),1,3-dimethylbenzene (meta-xylene), 1,4-dimetylbenzene (para-xylene),nitrobenzene, and the like; dipolar aprotic solvents, for example,acetonitrile, dimethylsulfoxide, N,N-dimethylformamide,N,N-diethylformamide, N,N-dimethylacetamide, N,N-diethylacetamide,N-methyl-2-pyrrolidinone, carbon disulfide, and hexamethylphosphoramide;and mixtures of one or more solvents.

The reaction can be conducted at any temperature sufficient to providethe desired products or desired products.

Step B

Step B relates to the conversion of a 5-aryl or5-heteroaryl-3-halo-2-cyanopyridine, A3, to a 5-aryl or5-heteroaryl-3-alkoxy-2-cyanopyridine, B.

Compound A3 is reacted with an alkoxide having the formula:

^(⊖)OR²

wherein R² is C₁-C₁₂ linear alkyl or C₃-C₁₂ branched alkyl. In oneembodiment of step B, intermediate A3 can be reacted with methoxideanion. The methoxide anion can be generated in situ, for example, by theaddition of an alkali metal to methanol. In one example, from 1equivalent to 10 equivalents of sodium metal based upon the amount of A3to be converted in Step B, is added to an excess of methanol. In anotherexample, an alkali metal is added to an excess of methanol, the solventremoved, and the resulting sodium methoxide retained for use when, forexample, Step B is conducted in a solvent other than methanol.

In another embodiment, the intermediate A3 can be reacted with ethoxideanion generated from ethanol. In still another embodiment, theintermediate A3 can be reacted with isopropoxy anion generated fromisopropanol.

As such, step B can be conducted at any temperature sufficient toprovide the desired products or desired products. In addition, step Bcan be conducted in any solvent or mixtures of solvents that do notreact with methoxide anion under the conditions chosen by theformulator.

Step C

Step C relates to the conversion of the 5-aryl or5-heteroaryl-3-alkoxy-2-cyanopyridine formed in step B to form a 5-arylor 5-heteroaryl-3-hydroxy-2-carboxypyridine, C, (5-aryl or5-heteroaryl-3-hydroxypicolinic acid). This conversion can be conductedin the presence of any acid capable of hydrolysis of the cyano moiety toa carboxylic acid moiety and the methoxy moiety to a hydroxyl moiety. Inone embodiment, 48% aqueous HBr can be used. In another embodiment, 37%aqueous HCl can be used.

The compounds having formula C can be isolated as the free acid or as asalt, for example, as a compound having the formula:

as further described herein. Depending upon the intended use of theproducts of step C, the formulator can proceed to step D or retain theproducts of step C for use in preparing admixtures of prolyl hydroxylaseinhibitors or for preparing prodrugs of prolyl hydroxylase inhibitors.

Step D

Step D relates to the reaction of the 5-aryl or5-heteroaryl-3-hydroxy-2-carboxypyridine formed in step C with acompound having formula D 1, wherein X is chosen from —OH, —OR³, —NR⁴R⁵or —OM¹ as defined herein above, to form one of the following:

i) a prolyl hydroxylase inhibitor;

ii) a prolyl hydroxylase inhibitor prodrug;

iii) an admixture of prolyl hydroxylase inhibitors;

iv) an admixture of prolyl hydroxylase inhibitor prodrugs; or

v) suitable pharmaceutical salts thereof.

One aspect of step D relates to formation of a prolyl hydroxylaseinhibitor according to the following scheme:

wherein R^(7a), R^(7b), R⁸ and the index n are defined herein above.

Another aspect of step D relate to formation of a prolyl hydroxylaseester prodrug according to the following scheme:

wherein R³, R^(7a), R^(7b), R⁸ and the index n are defined herein above.

A further aspect of step D relate to formation of a prolyl hydroxylaseamide prodrug according to the following scheme:

wherein R⁴, R⁵, R^(7a), R^(7b), R⁸ and the index n are defined hereinabove.

Step D relates to the coupling of a 5-aryl or5-heteroaryl-3-hydroxy-2-carboxy-pyridine, C, prepared in Step C with anamino acid, amino acid ester, or amino acid amide. Any coupling reagentcompatible with the 5-aryl or 5-heteroaryl-3-hydroxy-2-carboxy-pyridine,amino acid, amino acid ester, or amino acid amide can be used to preparethe desired prolyl hydroxylase inhibitors or prodrugs thereof.Non-limiting examples of coupling reagents includes carbonyldiimidazole(CDI), dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC),and ethyl-(N′,N′-dimethylamino)propylcarbodiimide (EDC),(benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate(BOP), (benzotriazol-1-yloxy)tripyrrolidinophosphoniumhexafluorophosphate (PyBOP),O-(benzotriazol-1-yl)-N,N,N′N′-tertaetyluronium hexafluorophosphate(HBTU), O-(benzotriazol-1-yl)-N,N,N′N′-tertamethyluroniumtetrafluoroborate (TBTU),O-(7-azabenzotriazol-1-yl)-N,N,N′N′-tetramethyluroniumhexafluorophosphate (HATU),O-(6-chlorobenzotriazol-1-yl)-N,N,N′N′-tetramethyluroniumhexafluorophosphate (HCTU),O-(3,4-dihydro-4-oxo-1,2,3-benzotriazine-3-yl)-N,N,N′N′-tetramethyluroniumhexafluorophosphate (TDBTU), and3-(diethylphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one (DEPBT). In oneiteration, wherein R⁸ is not hydrogen, step D can be conducted with asuitable reagent such as bromo-tris-pyrrolidino-phosphoniumhexafluorophosphate (PyBrOP).

A further iteration of the reaction outlined in step D utilizes an insitu generated mixed anhydride of the 5-aryl or5-heteroaryl-3-hydroxy-2-carboxypyridine, for example, reacting compoundC with a mixed anhydride forming reagent. Non-limiting examples includeisobutylchloro-formate (IBCF), ethylchoroformate,isopropylchloroformate, and the like. Other coupling reagents include2-chloro-3,6-dimethoxy-1,3,5-triazine, pivalolyl chloride andtriphosgene. In another iteration, acyl chlorides can be used toactivate the carbonyl moiety of compound C for the coupling exemplifiedin step D.

In a yet further embodiment pivaloyl chloride in THF are used tocatalyze the coupling reaction.

An organic or inorganic base can be used for conducting step D.Non-limiting examples of suitable organic bases includediisopropylethylamine, and the like.

Step D can be conducted in one or more solvents. Non-limiting examplesof solvents include dimethylformamide (DMF), diethylformamide (DEF),dimethylacetamide (DMA), diethylacetamide (DEA), dimethyl sulfoxide(DMSO), dioxane, and water. In one embodiment, a mixture of water andone or more polar organic solvents can be used, for example, DMF/water,DMSO/water, dioxane/water, DMF/dioxane/water, and the like.

In some embodiments of the disclosed process, due to the type ofsubstitution R¹⁰ on ring A, the formulator can form a prodrug prior thenfurther process the prodrug to the final prolyl hydroxylase inhibitor.For example, the intermediate C may comprise an R¹⁰ unit that has aprotecting group present, i.e., carbobenzyloxy, tert-butoxycarbonyl, andthe like. In such examples it can be more convenient for the formulatorto form the final product in prodrug form, remove the protecting groupthen in a Step E, hydrolyze the prodrug to the free acid. The hydrolysiscan be conducted in any suitable acid or base.

The conditions of Step D can be modified by the formulator to meet theproperties of the reagents.

Scheme I herein below outlines and Example 1 describes a non-limitingexample of the disclosed process for the preparation of a prolylhydroxylase ester pro-drug.

Example 1 Methyl{[5-(3-chlorophenyl)-3-hydroxypyridin-2-yl]amino}acetate (4)

Preparation of 5-(3-chlorophenyl)-3-chloro-2-cyanopyridine (1): To a 100mL round bottom flask adapted for magnetic stirring and equipped with anitrogen inlet was charged (3-chlorophenyl)boronic acid (5 g, 32 mmol),3,5-dichloro-2-cyanopyridine (5.8 g, 34 mmol), K₂CO₃ (5.5 g, 40 mmol),[1,1′-bis(diphenyphosphino)ferrocene]dichloro-palladium(II)[PdCl₂(dppf)](0.1 g, 0.13 mmol), dimethylformamide (50 mL) and water (5mL). The reaction solution was agitated and heated to 45° C. and held atthat temperature for 18 hours after which the reaction was determined tobe complete due to the disappearance of 3,5-dichloro-2-cyanopyridine asmeasured by TLC analysis using ethyl acetate/methanol (4:1) as themobile phase and UV 435 nm to visualize the reaction components. Thereaction solution was then cooled to room temperature and the contentspartitioned between ethyl acetate (250 mL) and saturated aqueous NaCl(100 mL). The organic phase was isolated and washed a second time withsaturated aqueous NaCl (100 mL). The organic phase was dried for 4 hoursover MgSO₄, the MgSO₄ removed by filtration and the solvent removedunder reduced pressure. The residue that remained was then slurried inmethanol (50 mL) at room temperature for 20 hours. The resulting solidwas collected by filtration and washed with cold methanol (50 mL) thenhexanes (60 mL) and dried to afford 5.8 g (73% yield) of an admixturecontaining a 96:4 ratio of the desired regioisomer. ¹H NMR (DMSO-d₆) δ9.12 (d, 1H), 8.70 (d, 1H), 8.03 (t, 1H) 7.88 (m, 1H), and 7.58 (m, 2H).

Preparation of 5-(3-chlorophenyl)-3-methoxy-2-cyanopyridine (2): To a500 mL round bottom flask adapted for magnetic stirring and fitted witha reflux condenser and nitrogen inlet was charged with5-(3-chlorophenyl)-3-chloro-2-cyanopyridine, 1, (10 g, 40 mmol), sodiummethoxide (13.8 mL, 60 mmol) and methanol (200 mL). With stirring, thereaction solution was heated to reflux for 20 hours. The reaction wasdetermined to be complete due to the disappearance of5-(3-chlorophenyl)-3-chloro-2-cyanopyridine as measured by TLC analysisusing hexane/ethyl acetate (6:3) as the mobile phase and UV 435 nm tovisualize the reaction components. The reaction mixture was cooled toroom temperature and combined with water (500 mL). A solid began toform. The mixture was cooled to 0° C. to 5° C. and stirred for 3 hours.The resulting solid was collected by filtration and washed with water,then hexane. The resulting cake was dried in vacuo at 40° C. to afford9.4 g (96% yield) of the desired product as an off-white solid. ¹H NMR(DMSO-d₆) δ 8.68 (d, 1H), 8.05 (d, 1H), 8.01 (s, 1H) 7.86 (m, 1H), 7.59(s, 1H), 7.57 (s, 1H) and 4.09 (s, 3H).

Preparation of 5-(3-chlorophenyl)-3-hydroxypyridine-2-carboxylic acid(3): To a 50 mL round bottom flask adapted for magnetic stirring andfitted with a reflux condenser was charged5-(3-chlorophenyl)-3-methoxy-2-cyanopyridine, 2, (1 g, 4 mmol) and a 48%aqueous solution of HBr (10 mL). While being stirred, the reactionsolution was heated to reflux for 20 hours. The reaction was determinedto be complete due to the disappearance of5-(3-chlorophenyl)-3-methoxy-2-cyanopyridine as measured by TLC analysisusing hexane/ethyl acetate (6:3) as the mobile phase and UV 435 nm tovisualize the reaction components. The reaction contents was then cooledto 0° C. to 5° C. with stirring and the pH was adjusted to approximately2 by the slow addition of 50% aqueous NaOH. Stirring was then continuedat 0° C. to 5° C. for 3 hours. The resulting solid was collected byfiltration and washed with water, then hexane. The resulting cake wasdried in vacuo at 40° C. to afford 1.03 g (quantitative yield) of thedesired product as an off-white solid. ¹H NMR (DMSO-d₆) δ 8.52 (d, 1H),7.99 (d, 1H), 7.95 (s, 1H) 7.81 (t, 1H), 7.57 (s, 1H), and 7.55 (s, 1H).

Preparation of methyl{[5-(3-chlorophenyl)-3-hydroxypyridin-2-yl]amino}acetate (4): To a 50 mLround bottom flask adapted for magnetic stirring and fitted with anitrogen inlet tube was charged5-(3-chlorophenyl)-3-hydroxypyridine-2-carboxylic acid, 3, (1 gm, 4mmol), N,N′-carbonyldiimidazole (CDI) (0.97 g, 6 mmol) and dimethylsulfoxide (5 mL). The reaction mixture was stirred at 45° C. for about 1hour then cooled to room temperature. Glycine methyl ester hydrochloride(1.15 g, 12 mmol) is added followed by the dropwise addition ofdiisopropylethylamine (3.2 mL, 19 mmol). The mixture was then stirredfor 2.5 hours at room temperature after which water (70 mL) was added.The contents of the reaction flask was cooled to 0° C. to 5° C. and 1NHCl was added until the solution pH is approximately 2. The solution wasextracted with dichloromethane (100 mL) and the organic layer was driedover MgSO₄ for 16 hours. Silica gel (3 g) is added and the solutionslurried for 2 hours after which the solids are removed by filtration.The filtrate is concentrated to dryness under reduced pressure and theresulting residue was slurried in methanol (10 mL) for two hours. Theresulting solid was collected by filtration and washed with coldmethanol (20 mL) then hexane and the resulting cake is dried to afford0.85 g of the desired product as an off-white solid. The filtrate wastreated to afford 0.026 g of the desired product as a second crop. Thecombined crops afford 0.88 g (68% yield) of the desired product. ¹H NMR(DMSO-d₆) δ 12.3 (s, 1H), 9.52 (t, 1H), 8.56 (d, 1H), 7.93 (s, 1H), 7.80(q, 2H), 7.55 (t, 2H), 4.12 (d, 2H), and 3.69 (s, 3H).

The formulator can readily scale up the above disclosed synthesis.Disclosed herein below is a synthesis wherein the disclosed process isscaled up for commercial use.

Example 2 Methyl{[5-(3-chlorophenyl)-3-hydroxypyridin-2-yl]amino}acetate (4)

Preparation of 5-(3-chlorophenyl)-3-chloro-2-cyanopyridine (1): A 20 Lreactor equipped with a mechanical stirrer, dip tube, thermometer andnitrogen inlet was charged with (3-chlorophenyl)boronic acid (550 g,3.52 mol), 3,5-dichloro-2-cyanopyridine (639 g, 3.69 mol), K₂CO₃ (5.5 g,40 mmol), [1,1′-bis(diphenyphosphino)ferrocene]dichloro-palladium(II)[PdCl₂(dppf)](11.5 g, 140 mmol), and dimethylformamide (3894 g, 4.125L). The reaction solution was agitated and purged with nitrogen throughthe dip-tube for 30 minutes. Degassed water (413 g) was then charged tothe reaction mixture while maintaining a temperature of less than 50° C.25 hours. The reaction was determined to be complete due to thedisappearance of 3,5-dichloro-2-cyanopyridine as measured by TLCanalysis using ethyl acetate/methanol (4:1) as the mobile phase and UV435 nm to visualize the reaction components. The reaction solution wasthen cooled to 5° C. and charged with heptane (940 g, 1.375 L) andagitated for 30 minutes. Water (5.5 L) was charged and the mixture wasfurther agitated for 1 hour as the temperature was allowed to rise to15° C. The solid product was isolated by filtration and washed withwater (5.5 L) followed by heptane (18881 g, 2750 ML). The resulting cakewas air dried under vacuum for 18 hours and then triturated with amixture of 2-propanol (6908 g, 8800 mL0 and heptane (1 g, 2200 mL0 at50° C. for 4 hours, cooled to ambient temperature and then agitated atambient temperature for 1 hour. The product was then isolated byfiltration and washed with cold 2-propanol (3450 g, 4395 mL) followed byheptane (3010 g, 4400 mL). The resulting solid was dried under highvacuum at 40° C. for 64 hours to afford 565.9 g (65% yield) of thedesired product as a beige solid. Purity by HPLC was 98.3. ¹H NMR(DMSO-d₆) δ 9.12 (d, 1H), 8.70 (d, 1H), 8.03 (t, 1H) 7.88 (m, 1H), and7.58 (m, 2H).

Preparation of 5-(3-chlorophenyl)-3-methoxy-2-cyanopyridine (2): A 20 Lreactor equipped with a mechanical stirred, condenser, thermometer andnitrogen inlet was charged with5-(3-chlorophenyl)-3-chloro-2-cyanopyridine, 1, (558 g, 2.24 mol) andsodium methoxide (25% solution in methanol, 726.0 g, 3.36 mol). Withagitation, the reaction solution was heated to reflux for 24 hours,resulting in a beige-colored suspension. The reaction was determined tobe complete due to the disappearance of5-(3-chlorophenyl)-3-chloro-2-cyanopyridine as measured by TLC analysisusing hexane/ethyl acetate (6:3) as the mobile phase and UV 435 nm tovisualize the reaction components. The reaction mixture was cooled to 5°C. and then charged with water (5580 mL). The resulting slurry wasagitated for 3 hours at 5° C. The solid product was isolated byfiltration and washed with water (5580 mL) until the filtrate had a pHof 7. The filter cake was air dried under vacuum for 16 hours. Thefilter cake was then charged back to the reactor and triturated in MeOH(2210 g, 2794 mL) for 1 hour at ambient temperature. The solid wascollected by filtration and washed with MeOH (882 g, 1116 mL, 5° C.)followed by heptane (205 mL, 300 mL), and dried under high vacuum at 45°C. for 72 hours to afford 448 g (82% yield) of the desired product as anoff-white solid. Purity by HPLC was 97.9%. ¹H NMR (DMSO-d₆) δ 8.68 (d,1H), 8.05 (d, 1H), 8.01 (s, 1H) 7.86 (m, 1H), 7.59 (s, 1H), 7.57 (s, 1H)and 4.09 (s, 3H).

Preparation of 5-(3-chlorophenyl)-3-hydroxypyridine-2-carboxylic acid(3): A 20 L reactor equipped with a mechanical stirrer, condenser,thermometer, nitrogen inlet and 25% aqueous NaOH trap was charged5-(3-chlorophenyl)-3-methoxy-2-cyanopyridine, 2, (440.6 g, 1.8 mol) and37% aqueous solution of HCl (5302 g). While being agitated, the reactionsolution was heated to 102° C. for 24 hours. Additional 37% aqueous HCl(2653 g) was added followed by agitation for 18 hours at 104° C. Thereaction contents was then cooled to 5° C., charged with water (4410 g)and then agitated at 0° C. for 16 hours. The resulting precipitatedproduct was isolated by filtration and washed with water until thefiltrate had a pH of 6 (about 8,000 L of water). The filter cake waspulled dry under reduced pressure for 2 hours. The cake was thentransferred back into the reactor and triturated in THF (1958 g, 2201mL) at ambient temperature for 2 hours. The solid product was thenisolated by filtration and washed with THF (778 g, 875 mL) and driedunder reduced pressure at 5° C. for 48 hours to afford 385 g (89% yield)of the desired product as an off-white solid. HPLC purity was 96.2%. ¹HNMR (DMSO-d₆) δ 8.52 (d, 1H), 7.99 (d, 1H), 7.95 (s, 1H) 7.81 (t, 1H),7.57 (s, 1H), and 7.55 (s, 1H).

Preparation of methyl{[5-(3-chlorophenyl)-3-hydroxypyridin-2-yl]amino}acetate (4): A 20 Lreactor equipped with a mechanical stirrer, condenser, thermometer andnitrogen inlet was charged with5-(3-chlorophenyl)-3-hydroxypyridine-2-carboxylic acid, 3, (380 g, 1.52mol) and diisopropylethylamine (DIPEA)(295 g, 2.28 mol). With agitation,the solution was cooled to 3° C. and charged with trimethylacetylchloride (275.7 g, 2.29 mol) while maintaining a temperature of lessthan 11° C., The mixture was then agitated at ambient temperature for 2hours. The mixture was then cooled to 10° C. and charged with a slurryof glycine methyl ester HCl (573.3 g, 4.57 mol) and THF (1689 g, 1900mL), then charged with DIPEA (590.2 g, 4.57 mol) and agitated at ambienttemperature for 16 hours. The mixture was then charged with EtOH (1500g, 1900 mL) and concentrated under reduced pressure to a reaction volumeof about 5.8 L. The EtOH addition and concentration was repeated twicemore. Water (3800 g) was then added and the mixture was agitated for 16hours at ambient temperature. The resulting solid product was isolatedby filtration and washed with a mixture of EtOH (300 g, 380 mL) andwater (380 g), followed by water (3800 g), dried under reduced pressurefor 18 hours at 50° C. to afforded 443 g (91% yield) of the desiredproduct as an off-white solid. Purity by HPLC was 98.9%. ¹H NMR(DMSO-d₆) δ 12.3 (s, 1H), 9.52 (t, 1H), 8.56 (d, 1H), 7.93 (s, 1H), 7.80(q, 2H), 7.55 (t, 2H), 4.12 (d, 2H), and 3.69 (s, 3H).

Scheme II herein below outlines and Example 2 describes a non-limitingexample of the disclosed process for preparing a prolyl hydroxylaseinhibitor from an ester prodrug.

Example 3 {[5-(3-Chlorophenyl)-3-hydroxypyridin-2-yl]amino}acetic acid(5)

Preparation of {[5-(3-chlorophenyl)-3-hydroxypyridin-2-yl]amino}aceticacid (5): To a 50 mL flask is charged methyl{[5-(3-chlorophenyl)-3-hydroxypyridin-2-yl]amino}-acetate, 4, (0.45 g,1.4 mmol), tetrahydrofuran (4.5 mL) and 1 M NaOH (4.5 mL, 4.5 mmol). Themixture was stirred for 2 hours at room temperature after which it wasdetermined by TLC analysis using hexane/ethyl acetate (6:3) as themobile phase and UV 435 nm to visualize the reaction components that thereaction was complete. The reaction solution was adjusted to pH 1 withconcentrated HCl and the solution was heated at 35° C. under vacuumuntil all of the tetrahydrofuran had been removed. A slurry forms as thesolution is concentrated. With efficient stirring the pH is adjusted to˜2 with the slow addition of 1 M NaOH. The solid which forms wascollected by filtration, washed with water, followed by hexane, thendried under vacuum to afford 0.38 g (88% yield) of the desired productas a white solid. ¹H NMR (DMSO-d₆) δ 12.84 (s, 1H), 12.39 (s, 1H), 9.39(t, 1H), 8.56 (d, 1H), 7.94 (s, 1H), 7.81 (m, 2H), 7.55 (q, 2H), and4.02 (d, 2H).

The formulator can readily scale up the above disclosed synthesis.Disclosed herein below is a synthesis wherein the disclosed process isscaled up for commercial use.

Example 4 {[5-(3-Chlorophenyl)-3-hydroxypyridin-2-yl]amino}acetic acid(5)

Preparation of {[5-(3-chlorophenyl)-3-hydroxypyridin-2-yl]amino}aceticacid (5): To a 20 L reactor equipped with a mechanical stirrer,condenser, thermometer and nitrogen inlet was charged methyl{[5-(3-chlorophenyl)-3-hydroxypyridin-2-yl]amino}-acetate, 4, (440 g,1.42 mol), tetrahydrofuran (3912 g, 4400 mL) and 1 M NaOH (4400 mL). Themixture was stirred for 2 hours at room temperature after which it wasdetermined by TLC analysis using hexane/ethyl acetate (6:3) as themobile phase and UV 435 nm to visualize the reaction components that thereaction was complete. The reaction solution was acidified to a pH of 2with slow addition of 2M HCl (2359 g). The resulting mixture wasconcentrated under reduced pressure to a volume of about 7.5 L. Ware(2210 g) was added and the solution cooled to ambient temperature andagitated for 18 hours. The solid product was isolated by filtration andwashed with water (6 L). the crude product was transferred back into thereactor and triturated with 2215 g of deionized water at 70° C. for 16hours. The mixture was cooled to ambient temperature, The solid productwas isolated by filtration and washed with water (500 mL) and driedunder reduced pressure at 70° C. for 20 hours to afford 368 g (87%yield) of the desired product as an off-white solid. Purity by HPLC was99.3%. ¹H NMR (DMSO-d₆) δ 12.84 (s, 1H), 12.39 (s, 1H), 9.39 (t, 1H),8.56 (d, 1H), 7.94 (s, 1H), 7.81 (m, 2H), 7.55 (q, 2H), and 4.02 (d,2H).

Scheme III herein below outlines and Example 3 describes a non-limitingexample of the disclosed process for preparing a prolyl hydroxylaseamide prodrug.

Example 55-(3-Chlorophenyl)-N-(2-amino-2-oxoethyl)-3-hydroxylpyridin-2-yl amide

Preparation of5-(3-chlorophenyl)-N-(2-amino-2-oxoethyl)-3-hydroxylpyridin-2-yl amide(6): To a solution of 5-(3-chlorophenyl)-3-hydroxypyridine-2-carboxylicacid, 3, (749 mg, 3 mmol) in DMF (20 mL) at room temperature under N₂ isadded 1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide (EDCI) (0.925 g,5.97 mmol) and 1-hydroxybenzo-triazole (HOBt) (0.806 g, 5.97 mmol). Theresulting solution is stirred for 15 minutes then 2-aminoacetamidehydrochloride (0.66 g, 5.97 mmol) and diisopropylethylamine (1.56 ml,8.96 mmol) are added. The reaction is monitored by TLC and when thereaction is complete the reaction mixture is concentrated under reducedpressure and H₂O added. The product can be isolated by normal work-up:The following data have been reported for compound (6). ¹H NMR (250 MHz,DMSO-d₆) δ ppm 12.46 (1H, s), 9.17 (1H, t, J=5.9 Hz), 8.55 (1H, d, J=2.0Hz), 7.93 (1H, d, J=0.9 Hz), 7.75-7.84 (2H, m), 7.49-7.60 (3H, m), 7.18(1H, s), 3.91 (2H, d, J=5.9 Hz). HPLC-MS: m/z 306 [M+H]⁺.

Scheme IV herein below depicts a non-limiting example the hydrolysis ofan amide pro-drug to a prolyl hydroxylase inhibitor after removal of aR¹⁰ protecting group.

While particular embodiments of the present disclosure have beenillustrated and described, it would be obvious to those skilled in theart that various other changes and modifications can be made withoutdeparting from the spirit and scope of the disclosure. It is thereforeintended to cover in the appended claims all such changes andmodifications that are within the scope of this disclosure.

What is claimed is:
 1. A compound having the formula:

wherein A is a ring chosen from: i) C₆ or C₁₀ aryl; or ii) C₁-C₉heteroaryl; R¹⁰ units represent at least one optionally presentsubstitutions for a ring hydrogen atom; or two R¹⁰ units can be takentogether to form a substituted or unsubstituted C₄-C₈ cycloalkyl ring, asubstituted or unsubstituted C₆ or C₁₀ aryl ring, a substituted orunsubstituted C₂-C₈ heterocyclic ring, or a substituted or unsubstitutedC₃ to C₅ heteroaryl ring, wherein the heterocyclic and heteroaryl ringscomprise one or more hetero atoms independently chosen from oxygen (O),nitrogen (N), or sulfur (S).
 2. The compound according to claim 1,wherein A is a C₆ aryl ring.
 3. The compound according to claim 1,wherein A is substituted by one or more R¹⁰ units independently chosenfrom: i) C₁-C₁₂ linear, C₃-C₁₂ branched, or C₃-C₁₂ cyclic alkyl,alkenyl, and alkynyl; ii) C₆ or C₁₀ aryl; iii) C₇ or C₁₁ alkylenearyl;iv) C₁-C₉ heterocyclic rings; v) C₁-C₉ heteroaryl rings; vi)—(CR^(102a)R^(102b))_(a)OR¹⁰¹; vii) —(CR^(102a)R^(102b))_(a)C(O)R¹⁰¹;viii) —(CR^(102a)R^(102b))_(a)C(O)OR¹⁰¹; ix)—(CR^(102a)R^(102b))_(a)C(O)N(R¹⁰¹)₂; x)—(CR^(102a)R^(102b))_(a)N(R¹⁰¹)C(O)R¹⁰¹; xi)—(CR^(102a)R^(102b))_(a)N(R¹⁰¹)C(O)₂R¹⁰¹; xii)—(CR^(102a)R^(102b))_(a)N(R¹⁰¹)₂; xiii) halogen; xiv)—(CR^(102a)R^(102b))_(I); xv) —(CR^(102a)R^(102b))_(a)NO₂; xvi)—(CH_(j′)X_(k′))_(a)CH_(j)X_(k); wherein X is halogen, the index j is aninteger from 0 to 2, j+k=3; the index j′ is an integer from 0 to 2,j′+k′=2; xvii) —(CR^(102a)R^(102b))_(a)SR¹⁰¹; xviii)—(CR^(102a)R^(102b))_(a)SO₂R¹⁰¹; and xix)—(CR^(102a)R^(102b))_(a)SO₃R¹⁰¹; wherein each R¹⁰¹ is independentlyhydrogen, substituted or unsubstituted C₁-C₆ linear, C₃-C₆ branched, orC₃-C₆ cyclic alkyl, phenyl, benzyl, heterocyclic, or heteroaryl; or twoR¹⁰¹ units can be taken together to form a ring comprising 3-7 atoms;R^(102a) and R^(102b) are each independently hydrogen or C₁-C₄ linear orC₃-C₄ branched alkyl; the index “a” is from 0 to
 4. 4. The compoundaccording to claim 1, wherein A is substituted by one or more R¹⁰ unitsindependently chosen from: i) C₁-C₁₂ linear, C₃-C₁₂ branched or C₃-C₁₂cyclic alkyl; ii) C₁-C₁₂ linear, C₃-C₁₂ branched or C₃-C₁₂ cyclicalkoxy; or iii) halogen.
 5. The compound according to claim 1, whereinring A is chosen from 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl,2,3-difluorophenyl, 3,4-difluoro-phenyl, 3,5-difluorophenyl,2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,3-dichlorophenyl,3,4-dichlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromo-phenyl,3,5-dichlorophenyl, 2,3,4-trifluorophenyl, 2,3,5-trifluorophenyl,2,3,6-trifluorophenyl, 2,4,5-trifluorophenyl, 2,4,6-trifluorophenyl,2,4-dichlorophenyl, 2,5-dichlorophenyl, 2,6-dichlorophenyl,3,4-dichlorophenyl, 2,3,4-trichlorophenyl, 2,3,5-trichlorophenyl,2,3,6-trichlorophenyl, 2,4,5-trichlorophenyl, 3,4,5-trichloro-phenyl,and 2,4,6-trichlorophenyl.
 6. The compound according to claim 1, whereinring A is chosen from 2-chloro-3-methylphenyl, 2-chloro-4-methylphenyl,2-chloro-5-methylphenyl, 2-chloro-6-methylphenyl,3-chloro-2-methylphenyl, 3-chloro-4-methylphenyl,3-chloro-5-methylphenyl, 3-chloro-6-methyl-phenyl,2-fluoro-3-methylphenyl, 2-fluoro-4-methylphenyl,2-fluoro-5-methylphenyl, 2-fluoro-6-methylphenyl,3-fluoro-2-methylphenyl, 3-fluoro-4-methylphenyl,3-fluoro-5-methylphenyl, and 3-fluoro-6-methylphenyl.
 7. The compoundaccording to claim 1, wherein ring A is chosen from 3-chlorophenyl,3-fluorophenyl, 3-trifluoromethylphenyl, and 3-chloro-6-methylphenyl. 8.The compound according to claim 1, wherein two R¹⁰ units are be takentogether to form a substituted or unsubstituted C₂-C₈ heterocyclic ring,wherein the heterocyclic ring comprises one or more hetero atomsindependently chosen from oxygen (O), nitrogen (N), or sulfur (S). 9.The compound according to claim 1, wherein two R¹⁰ units are takentogether to form an A ring that has a formula chosen from:


10. A compound having the formula:

wherein M is a salt forming cation and N represents the cationic chargeon M; A is a ring chosen from: i) C₆ or C₁₀ aryl; or ii) C₁-C₉heteroaryl; R¹⁰ units represent at least one optionally presentsubstitutions for a ring hydrogen atom; or two R¹⁰ units can be takentogether to form a substituted or unsubstituted C₄-C₈ cycloalkyl ring, asubstituted or unsubstituted C₆ or C₁₀ aryl ring, a substituted orunsubstituted C₂-C₈ heterocyclic ring, or a substituted or unsubstitutedC₃ to C₅ heteroaryl ring, wherein the heterocyclic and heteroaryl ringscomprise one or more hetero atoms independently chosen from oxygen (O),nitrogen (N), or sulfur (S). L is a linking unit having the formula:—(CR^(7a)R^(7b))_(n)— R^(7a) and R^(7b) are each independently: i)hydrogen; or ii) C₁-C₆ linear, C₃-C₆ branched or C₃-C₆ cyclic alkyl; R⁸is chosen from hydrogen, methyl, or ethyl; and the index n is an integerfrom 1 to
 4. 11. The compound according to claim 10, wherein A is a C₆aryl ring.
 12. The compound according to claim 10, wherein A issubstituted by one or more R¹⁰ units independently chosen from: i)C₁-C₁₂ linear, C₃-C₁₂ branched, or C₃-C₁₂ cyclic alkyl, alkenyl, andalkynyl; ii) C₆ or C₁₀ aryl; iii) C₇ or C₁₁ alkylenearyl; iv) C₁-C₉heterocyclic rings; v) C₁-C₉ heteroaryl rings; vi)—(CR^(102a)R^(102b))_(a)OR¹⁰¹; vii) —(CR^(102a)R^(102b))_(a)C(O)R¹⁰¹;viii) —(CR^(102a)R^(102b))_(a)C(O)OR¹⁰¹; ix)—(CR^(102a)R^(102b))_(a)C(O)N(R¹⁰¹)₂; x)—(CR^(102a)R^(102b))_(a)N(R¹⁰¹)C(O)R¹⁰¹; xi)—(CR^(102a)R^(102b))_(a)N(R¹⁰¹)C(O)₂R¹⁰¹; xii)—(CR^(102a)R^(102b))_(a)N(R¹⁰¹)₂; xiii) halogen; xiv)—(CR^(102a)R^(102b))_(I); xv) —(CR^(102a)R^(102b))_(a)NO₂; xvi)—(CH_(j′)X_(k′))_(a)CH_(j)X_(k); wherein X is halogen, the index j is aninteger from 0 to 2, j+k=3; the index j′ is an integer from 0 to 2,j′+k′=2; xvii) —(CR^(102a)R^(102b))_(a)SR¹⁰¹; xviii)—(CR^(102a)R^(102b))_(a)SO₂R¹⁰¹; and xix)—(CR^(102a)R^(102b))_(a)SO₃R¹⁰¹; wherein each R¹⁰¹ is independentlyhydrogen, substituted or unsubstituted C₁-C₆ linear, C₃-C₆ branched, orC₃-C₆ cyclic alkyl, phenyl, benzyl, heterocyclic, or heteroaryl; or twoR¹⁰¹ units can be taken together to form a ring comprising 3-7 atoms;R^(102a) and R^(102b) are each independently hydrogen or C₁-C₄ linear orC₃-C₄ branched alkyl; the index “a” is from 0 to
 4. 13. The compoundaccording to claim 10, wherein A is substituted by one or more R¹⁰ unitsindependently chosen from: i) C₁-C₁₂ linear, C₃-C₁₂ branched or C₃-C₁₂cyclic alkyl; ii) C₁-C₁₂ linear, C₃-C₁₂ branched or C₃-C₁₂ cyclicalkoxy; or iii) halogen.
 14. The compound according to claim 10, whereinring A is chosen from 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl,2,3-difluorophenyl, 3,4-difluoro-phenyl, 3,5-difluorophenyl,2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,3-dichlorophenyl,3,4-dichlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromo-phenyl,3,5-dichlorophenyl, 2,3,4-trifluorophenyl, 2,3,5-trifluorophenyl,2,3,6-trifluorophenyl, 2,4,5-trifluorophenyl, 2,4,6-trifluorophenyl,2,4-dichlorophenyl, 2,5-dichlorophenyl, 2,6-dichlorophenyl,3,4-dichlorophenyl, 2,3,4-trichlorophenyl, 2,3,5-trichlorophenyl,2,3,6-trichlorophenyl, 2,4,5-trichlorophenyl, 3,4,5-trichloro-phenyl,and 2,4,6-trichlorophenyl.
 15. The compound according to claim 10,wherein ring A is chosen from 2-chloro-3-methylphenyl,2-chloro-4-methylphenyl, 2-chloro-5-methylphenyl,2-chloro-6-methylphenyl, 3-chloro-2-methylphenyl,3-chloro-4-methylphenyl, 3-chloro-5-methylphenyl,3-chloro-6-methyl-phenyl, 2-fluoro-3-methylphenyl,2-fluoro-4-methylphenyl, 2-fluoro-5-methylphenyl,2-fluoro-6-methylphenyl, 3-fluoro-2-methylphenyl,3-fluoro-4-methylphenyl, 3-fluoro-5-methylphenyl, and3-fluoro-6-methylphenyl.
 16. The compound according to claim 10, whereinring A is chosen from 3-chlorophenyl, 3-fluorophenyl,3-trifluoromethylphenyl, and 3-chloro-6-methylphenyl.
 17. The compoundaccording to claim 10, wherein two R¹⁰ units are be taken together toform a substituted or unsubstituted C₂-C₈ heterocyclic ring, wherein theheterocyclic ring comprises one or more hetero atoms independentlychosen from oxygen (O), nitrogen (N), or sulfur (S).
 18. The compoundaccording to claim 10, wherein two R¹⁰ units are taken together to forman A ring that has a formula chosen from: